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The identification of Helicobacter pylori (H. pylori) infection as the primary etiology of gastroduodenal diseases represents a significant advancement in the field of gastroenterology. The management of these diseases has undergone a substantial transformation, and antibiotic treatment is now universally applicable. H. pylori has been the subject of numerous investigations to determine the prevalence of antibiotic resistance. However, many of these studies are limited, particularly regarding the number and representativeness of the strains assessed. Genetic and physiological modifications, such as gene mutations, efflux pump alterations, biofilm formation, and coccoid formation, contribute to the observed resistance. Our review focuses on the emergence of antibiotic-resistant strains, particularly emphasizing the various modifications of H. pylori that confer this resistance. In conclusion, we elucidate the challenges, potential solutions, and prospects in this field, providing researchers with the knowledge necessary to overcome the resistance exhibited by H. pylori.
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Introduction
Helicobacter pylori (H. pylori) is a prevalent gram-negative microaerobic pathogen especially in developing countries [1]. Recent estimates place the H. pylori infection rate in developing nations near fifty percent [2]. The reported infection rates of H. pylori in West Asia, Africa, and South America are 66.6%, 70.1%, and 69.4%, respectively [3]. The colonization of gastric mucosa by H. pylori in 50–70% of the worldwide population raises the likelihood of developing chronic gastritis, peptic ulcer, gastric cancer, and gastric mucosa-associated lymphoid tissue (MALT) lymphoma [4]. In the absence of an effective vaccine, the primary method of reducing bacterial transmission, healing gastric lesions in infected individuals, and preventing the development of gastric cancer is to treat the H. pylori infection [5]. Moreover, in contrast to prior notions of H. pylori management, a substantial transformation has occurred since the 2015 Kyoto H. pylori conference consensus, which advised the eradication of all H. pylori infections unless there exist compelling justifications for non-eradication, including co-morbidities, high rates of re-infection within the nation, or conflicting societal health priorities [6]. As illustrated in Fig. 1, the main modes of intra-individual transmission encompass the gastro-oral, oral-oral, and fecal–oral routes [7]. Other methods of disease dispersion include iatrogenic transmission and breastfeeding. Small nucleotide sequences can reveal transmission pathways and directions between individuals due to the substantial genetic diversity of H. pylori. Seven-gene multilocus sequence typing [8] and, more recently, whole-genome sequence analysis [9] have facilitated the comprehension of how H. pylori disseminates within families, providing valuable insights for confronting epidemiological challenges.
Fig. 1
Proposed modes of transmission for H. pylori. Five of the suggested routes exemplify direct transmission between individuals (breastfeeding, iatrogenic, oral-oral, gastro-oral, and fecal–oral), whereas the other three necessitate an environmental reservoir in the intervening stages. This figure was created using BioRender
H. pylori is treated with a variety of antibiotics, including amoxicillin (AMX), clarithromycin (CLR), metronidazole (MNZ), tetracycline (TET), furazolidone (FR), levofloxacin (LVX), and rifabutin (RFB), which are administered in combination. The AMX, a β-lactam antibiotic, affects bacterial cell wall formation [10]. However, resistance may develop via changes in penicillin-binding proteins.The CLR, a macrolide, suppresses protein synthesis by targeting the 23S rRNA; nevertheless, resistance is usually caused by point mutations in the 23S rRNA gene. The MNZ, a nitroimidazole, acts intracellularly to destroy bacterial DNA, but resistance develops via changes in the rdxA and frxA genes [11]. The TET binds to the 30S ribosomal subunit and inhibits translation, with resistance related to changes in the 16S rRNA gene [12]. The FR, a nitrofuran, produces reactive intermediates that harm bacterial components, although resistance mechanisms are poorly known. The LVX, a fluoroquinolone, inhibits DNA gyrase and topoisomerase IV; however, resistance develops via gyrA mutations. The RFB inhibits RNA polymerase, but mutations in the rpoB gene may provide resistance [10]. The rising resistance of H. pylori to various antibiotics highlights the need for customized therapy, innovative antimicrobial drugs, and other treatment options to improve eradication rates [13].
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H. pylori's antibiotic resistance is crucial given that it is one of the most common causes of bacterial infections worldwide, affecting millions of people each year [14]. Furthermore, overuse or misuse of antibiotics may contribute to the development of antimicrobial resistance in H. pylori and other bacteria, creating serious public health concerns [15]. The World Health Organization has designated H. pylori as a serious threat to human health because of its resistance to most current treatment procedures [16].
The molecular processes behind antibiotic resistance in H. pylori infection are diverse and complicated [17]. Several strategies have been proposed to assist H. pylori antibiotic resistance, including genetic defects within the bacterium and physiological changes that may increase efflux pump synthesis in bacterial cells [10]. Another potential resistance mechanism is cellular adaptation connected to biofilm or coccoid formation, which prevents drugs from entering bacterial cells [18]. Numerous resistance routes may synergistically confer multidrug resistance (MDR) in H. pylori, complicating eradication attempts and emphasizing the need for innovative treatments [19]. In conclusion, we highlight the obstacles, prospective solutions, and possibilities in this sector, providing researchers with the knowledge essential to overcome the resistance displayed by H. pylori.
Emerging antibiotic-resistant strains
Lower income, lower education level, housing congestion, rural residence, ethnicity, use of tanks for water, smoking, alcohol consumption, consumption of raw vegetables or spicy meals, inadequate living conditions, and hygiene practices are all risk factors for H. pylori infection, particularly in Asia [3, 21]. There is a growing prevalence of H. pylori infection in developing nations, as indicated by the data presented in Fig. 2 [22, 23]. The prevalence of infection in underdeveloped countries is approximately 25%, which is higher than in Western countries such as the United States, England, and Canada [24]. Nevertheless, it is worth noting that around 85% of individuals who were infected with H. pylori did not experience any associated issues or symptoms. Geographic variations have been discovered to be connected with specific putative virulence genes of H. pylori [24]. Compared to high-income countries (21.7%), infection rates among children and adults were higher in low- and middle-income countries or regions (43.2%) during the period from 2014 to 2020 [25]. However, this disparity was diminished in the Western Pacific region [20]. In terms of the age factor, the infection rates of children are lower than those of adults, and they are higher in developing rural areas than in metropolitan areas. Despite advancements in sanitation and socioeconomic conditions, 34% of children worldwide were discovered to have H. pylori infections between 2014 and 2020 [20, 25].
Fig. 2
A global map illustrating the global distribution of H. pylori infection. The predominance has been visually shown using areas that are encircled with colors. The data categories are as follows: black (70%), green (55–69%), red (35–54%), blue (21–34%), brown (20%), and purple (not applicable) [22, 23]. This map was created using BioRender
H. pylori is eradicated by combining two to three antibiotics, including a restricted number of options such as AMX, CLR, MNZ, TET, LVX, and RFB, with an acid-suppressant, with or without bismuth [26, 27]. In contrast, the rate of effective H. pylori eradication has declined over the past few decades, coinciding with the rise in antibiotic resistance [15, 16, 28‐30]. H. pylori antibiotic resistance is especially concerning, given that it is one of the leading causes of bacterial infections across the globe, impacting millions of individuals annually [3, 31]. The molecular pathways responsible for antibiotic resistance in H. pylori infection are varied and intricate [32].
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Antibiotic resistance in H. pylori has arisen as a major public health concern, with significant variation depending on location [10]. The incidence of antibiotic resistance is influenced by a variety of factors, including antibiotic use, healthcare laws, and regional economic situations [33]. In Asia, more than half of H. pylori infections are resistant to drugs, including CLR, MNZ, and LVX [34]. This is mostly due to poor antibiotic usage and the frequency of self-medication. In Africa, a similar scenario persists, with high resistance, notably to MNZ. This is most likely owing to the widespread use of MNZ to treat parasitic illnesses, as well as the lack of tight antibiotic use regulations [35]. However, Europe has a diverse topography of resistance. Southern and Eastern Europe frequently have higher rates than Northern and Western Europe, which may reflect differences in antibiotic prescribing policies among physicians [36]. Antibiotic resistance is spreading across the Americas, notably in Latin America, where MDR illnesses are becoming more common [37]. In contrast, Oceania has lower rates of resistance, possibly due to stricter antibiotic usage and prescribing practices [38].
Resistance in H. pylori can take several forms, ranging from resistance to a single antibiotic, such as CLR or MNZ, to dual resistance, which usually includes both CLR and MNZ [10]. This dual resistance severely reduces the efficacy of standard H. pylori therapy. However, there is growing worry about the development of the MDR, which is defined as resistance to three or more antibiotics. These multidrug-resistant H. pylori strains are far more difficult to treat with traditional methods, prompting the development of new therapeutic techniques.
H. pylori can acquire resistance to treatment through two main mechanisms: primary resistance and secondary resistance [39]. Primary resistance develops in people who have not previously undergone therapy [40]. This sort of resistance is typically caused by an overuse of antibiotics in a community. It is especially common in areas where antibiotics are easily available over the counter or prescribed for diseases unrelated to bacterial infections. People who have previously sought but failed to remove H. pylori develop secondary resistance [39]. This might happen when the treatment regimen is poor or when people do not take their medications as advised. Repeated exposure to ineffective treatments creates pressure, facilitating the establishment of super-resistant strains and complicating the eradication of the sickness [41].
To address the growing problem of H. pylori bacteria acquiring antibiotic resistance, it is critical to build monitoring systems tailored to local sites [10]. These techniques are critical for monitoring the progression of resistance and supporting clinicians in selecting the best therapy. Furthermore, it is critical to create campaigns that encourage the prudent use of antibiotics. This will prevent unnecessary antibiotic use and lessen the pressures that contribute to resistance. Using molecular tests to determine antibiotic susceptibility before starting therapy may increase the chance of successful eradication by allowing doctors to tailor medicine to each patient [42]. Failure to respond quickly and collectively will accelerate H. pylori resistance to antibiotics, reducing treatment efficacy, raising the risk of serious gastrointestinal problems, and putting significant pressure on global healthcare systems.
Fundamental mechanisms driving drug resistance in H. pylori
Physiological modifications
Physiological effects describe the alterations or reactions that occur in living organisms due to interactions with their surroundings. These impacts are crucial for maintaining life and may happen immediately.
Efflux pump system
Efflux pumps are proteins that transfer substances across bacteria's cytoplasmic membrane. They regulate the interior environment by extruding poisonous compounds, quorum sensing molecules (autoinducers), biofilm matrix subunits, and bacterial virulence factors. They are regarded as one of the most frequent resistance mechanisms among a wide variety of harmful bacteria [44]. In the early 1990s, the discovery of MDR pumps in E. coli and Pseudomonas aeruginosa, represented by the resistance-nodulation-division (RND) superfamily exporters, significantly improved our knowledge of resistance mechanisms [45‐47]. In contrast, the role of efflux pumps in H. pylori resistance to MNZ was first demonstrated in 2005 [48]. At present, bacteria possess six distinct efflux pump families: the ATP-binding cassette (ABC) superfamily, the small multidrug resistance (SMR) family, the major facilitator superfamily (MFS), the proteobacterial antimicrobial compound efflux (PACE) family, the RND superfamily, and the multidrug and toxin extrusion (MATE) family [44, 49].
Primary transporters need biological energy tos move substrate across the membrane, while passive transporters do not [50‐52]. The ABC superfamily has a key active transporter that has been widely studied. In contrast, several different superfamilies exhibit secondary active transport. These are MFS, SMR, RND, and MATE. While several efflux pump families have been investigated, more research is needed on H. pylori efflux pumps. Gene analysis revealed 144 putative translocases in H. pylori, all of which were proven to belong to the RND, MFS, MATE, and ABC families (Fig. 3A) [53, 54].
Fig. 3
Summary of physiological changes involved in H. pylori antibiotic resistance, A The four confirmed multidrug efflux pumps families which have been associated with bacterial drug resistance: resistance-nodulation-division (RND), major facilitators (MFS type), drug/metabolite transporters (DMT type), ATP-binding cassette (ABC) transporters, extrusion of various medications and hazardous substances (MATE category), (B) biofilm formation, and (D) coccoid formation. This figure was created using BioRender
Until now, most H. pylori transporters are not well described in their processes, structures, and activities [54, 55]. Surprisingly, little is known about H. pylori SMR transporters. The prevalence of efflux genes in bacterial genomes raises the topic of the significance of SMR pumps in H. pylori multidrug resistance. Identifying particular EPIs is crucial for efficiently eliminating H. pylori due to their structural similarity and extensive substrate specificity [56]. To improve the efficacy of present H. pylori therapies, efflux pumps must be classified, and particular translocases identified.
Efflux pumps are proteins that transfer substances across the bacterial cytoplasmic membrane, regulating the interior environment by extruding poisonous compounds, quorum sensing molecules (autoinducers), biofilm formation molecules, and bacterial virulence factors [57, 58]. They are regarded as one of the most frequent resistance mechanisms among a wide variety of harmful bacteria [59].
In the early 1990s, the discovery of the MDR pumps in E. coli and Pseudomonas aeruginosa, represented by the RND superfamily exporters, significantly improved our knowledge of resistance mechanisms [60, 61]. In contrast, the role of efflux pumps in H. pylori resistance to MNZ was first demonstrated in 2005 [11]. At present, bacteria possess six distinct efflux pump families: the ABC superfamily, the SMR family, the MFS, the PACE family, the RND superfamily, and the MATE family [62].
Efflux pumps can be classified based on their energy source. Primary transporters, such as those in the ABC superfamily, require biological energy to move substrates across the membrane, whereas passive transporters do not [63]. The ABC superfamily has been widely studied as a key active transporter. In contrast, several other superfamilies, including MFS, SMR, RND, and MATE, exhibit secondary active transport [11].
Although several efflux pump families have been investigated, more research is needed on H. pylori efflux pumps [54]. Gene analysis has revealed 144 putative translocases in H. pylori, all of which belong to the RND, MFS, MATE, and ABC families [54]. However, most H. pylori transporters remain poorly described in terms of their processes, structures, and activities [64]. Notably, little is known about H. pylori SMR transporters. The prevalence of efflux genes in bacterial genomes raises the question of the significance of SMR pumps in H. pylori multidrug resistance.
Identifying specific efflux pump inhibitors (EPIs) is crucial for efficiently eliminating H. pylori due to their structural similarity and extensive substrate specificity [54]. To improve the efficacy of current H. pylori therapy efflux pumps must be classified, and specific translocases must be identified. Efflux pumps can expel a wide range of drugs and have been identified as key components of multidrug resistance in various bacteria [65], including H. pylori [54].
Additionally, efflux pumps contribute to biofilm antimicrobial resistance, with evidence found in multiple bacteria, including Pseudomonas aeruginosa [66], E. coli [67], and Candida albicans [68]. Yonezawa et al. [69] observed that in H. pylori clinical MDR strains (C-MDR), biofilm cells expressed more efflux pump genes than planktonic cells. While certain efflux transporters have been discovered in H. pylori [70]their activities, particularly in H. pylori biofilm formation, require further investigation.
Furthermore, recent findings by Gong [71] suggest that various resistance gene point mutations may have different effects on efflux pump gene expression. Knockout of efflux pump genes may delay or prevent antibiotic resistance gene changes to some extent and may also reverse phenotypic resistance to CLR and MNZ in specific strains. Additionally, Alfaray et al. [72] identified 29 putative efflux pump-related antimicrobial resistance (AMR) genes in H. pylori, which were generally classified as part of the Core Genome of H. pylori (ARG-CORE). The distribution of antimicrobial resistance genes (ARGs) is consistent across geographical areas and H. pylori populations. However, certain ARGs exhibit distinct distributions and are found only in specific regions or populations.
Biofilm formation
A biofilm is a cluster of microbial cells intricately organized and encircled by a matrix they produce independently [73]. This matrix establishes a boundary between the biofilm and its environs [74]. This arrangement enhances the survival of microbial producers and facilitates their collection in challenging environments [75]. In contrast to planktonic forms, the biofilm state of microbial cells is characterized by a distinct rate of proliferation, metabolism, and morphology, as well as a modified gene expression profile [76]. The term "biofilm" has been extensively employed in environmental microbiology due to the prevalence of biofilms in natural environments [77]. At present, there is a greater emphasis on their presence within the human body, as they have the capacity to influence the onset of disorders and the maintenance of good health [78]. Biofilms are responsible for over 80% of all human infections and 60% of chronic ones, according to the US National Institutes of Health and the US Centers for Disease Control and Prevention [79].
Biofilm is approximately one thousand times more resistant to antibiotics and other antimicrobial agents than planktonic forms [80‐82]. Various factors, including persister cells and a reduced growth rate, influence this phenotype. Additionally, the mobility of antimicrobial substances in the encircling environment is restricted by a dense matrix layer [73]. Numerous scientific investigations have demonstrated a correlation between the composition of the biofilm matrix and antibiotic resistance [73, 83, 84]. Additionally, there is evidence that the prevalence of antibiotic resistance to specific antibiotic groups [85‐87] or even multidrug resistance [73, 88‐91] is associated with the thickness and intensity of biostructure production. Consequently, certain scientists believe that the primary factor in developing an effective antimicrobial treatment is the comprehension of the mechanisms that drive the growth and maturation of biofilms [73, 75].
The physiological mechanisms responsible for producing H. pylori biofilms are primarily unclear [92]. The scientific community has long denied bacterial biofilms, leading to our current predicament [93, 94]. Fortunately, this impasse has been gradually resolved over the past five years, leading to the publication of substantial research that delineates the biofilm forms of this bacterium [95]. According to original research on the subject, biofilm H. pylori forms exhibit significantly higher resistance levels to numerous antibiotics that are employed in clinical settings (Fig. 3B) [96‐99]. The proteins and extracellular DNA (eDNA) that constitute H. pylori's biofilm matrix have also been identified in publications [73, 100]. These results may explain the previously observed decrease in antibiotic sensitivity [101]. The scientific community was motivated to investigate this critical issue further by these findings, which confirmed the previous hypothesis that biofilm substantially impacted the elimination of H. pylori [95]. Ultimately, research conducted by Krzyżek et al., [73]and [102] revealed that clinical H. pylori strains that exhibited resistance to CLR had a wide range of phenotypic traits that may be interpreted as the capacity to create robust biofilms.
The coccoid formation
Gram-negative rods frequently generate coccoid forms in response to stress, such as starvation [103]. Electron microscopy investigations have demonstrated that H. pylori can assume three distinct forms [104‐106]. The transformation of H. pylori from the bacillary to the coccoid form in response to in vitro exposure to diverse antimicrobial agents has been demonstrated in numerous studies (Fig. 3C) [107]. A dissolved cell membrane and degenerative organelles characterize the nonviable coccoid forms. The viable coccoid is frequently more compact and diminutive than the degenerative coccoid forms. According to West et al., [108], the culturable variants of H. pylori can be cultured in artificial seawater for a period exceeding seven days and in distilled water and salinity for a period exceeding fourteen days. Shahamat et al., [109] conducted a study that indicated that certain varieties of H. pylori can survive in pure water for more than ten days, while nonculturable coccoid H. pylori can survive for up to a year. Over seven days, the identical H. pylori strain maintained in a nutrient-rich medium did not perform as well as that maintained in natural saline or deep groundwater at 4 °C [110]. As per their research, culturable genotypes of H. pylori can persist in water for up to a week and perform better in environments devoid of artificial nutrients than in artificially wealthy ones. The spiral forms likely did not contaminate the fractions then, as the nonculturable coccoid form survived for months.
Antibiotic concentrations such as CLA, MNZ, ERY, and AMX can cause this morphological alteration [111, 112]. AMX, effective against H. pylori in vitro, has the greatest induction effect [111, 113]. However, morphological analysis of the cultures reveals that bacillary forms diminish in favor of coccoid forms [111, 113]. Berry et al. [111] discovered that AMX cleared bacillary H. pylori with a 10 × MIC but also promoted coccoid forms. Coccoid forms have different penicillin-binding protein profiles than bacillary forms, making them less likely to respond to β-lactam antibiotics [114]. Thus, after eradication, certain H. pylori cells may become coccoid and resistant to antibacterial treatments. This may explain recurrence and treatment failure [115]. The coccoid form, like the bacillary form, encodes important virulence genes, including ureA, ureB, hpaA, vacA, cagA, cagE, and babA [112, 116]. This long-term expression is likely to play a role in persistent severe gastrointestinal problems.
A genetic mutation
Significant contributors to the antibiotic resistance mode are mutations in critical functional genes of H. pylori [117]. Consequently, most of these gene mutations that confer resistance to a particular class of antibiotic have been discussed (Fig. 4). The following are H. pylori genes whose mutations contribute to the bacteria's antibiotic resistance.
Fig. 4
Summary of genetic changes (genes mutations) involved in H. pylori antibiotic resistance; The mutation of the penicillin-binding proteins (PBP) gene is a prevalent method by which H. pylori strains obtain resistance to amoxicillin (AMX), (B) The tetracycline (TET) resistance identified in H. pylori is due to point mutations in the 16S rRNA gene that prevent TET from binding to the primary binding site of the 16S ribosome. The presence of point mutations in the 23S rRNA gene is indicative of clarithromycin (CLR) resistance, (C) Resistance to levofloxacin (LVX) may be caused by mutations in the quinolone resistance determining region (QRDR), which contains the genes gyrA and gyrB, which encode bacterial gyrase subunits and finally, (D) Resistance mechanisms of H. pylori towards furazolidone (FR) are predominantly attributed to single nucleotide mutations in the target genes of rdxA, frxA, and fdxB. Conversely, resistance to metronidazole (MNZ) is caused by alterations in porD and oorD. This figure was created using BioRender
Bacterial cell division is a complicated multimolecular process that requires PBPs to synthesize new peptidoglycan during cell wall elongation and septum formation [118]. The PBPs change and polymerize peptidoglycan, the part of the bacterial cell wall that bears the brunt of the stress [119, 120]. PBPs, in conjunction with cytoskeleton proteins that regulate cell morphology, impact the visual characteristics of the peptidoglycan exoskeleton [120]. According to genetic and microscopic investigations, class A and class B PBPs have distinct morphological roles, which point to differential protein localization and interactions with certain cell components as the mechanism of shape determination [120].
AMX, a semisynthetic penicillin with broad-spectrum β-lactam antibiotic properties, is commonly employed as the initial treatment in current therapeutic regimens for eradicating H. pylori [55]. The AMX inhibits the formation of cell wall mucins in H. pylori cells by binding to PBPs, leading to cell enlargement and cracking [55]. In H. pylori strains, mutation of PBP genes is a frequently seen mechanism for developing resistance to AMX [55]. Researchers have discovered nine distinct PBPs in H. pylori. These include three PBPs with large molecular weights, namely PBP1 (66 kDa), PBP2 (63 kDa), and PBP3 (60 kDa), as well as six PBPs with low molecular weights known as PBP4-9 [55]. PBP1A, a subtype of PBP1, has glycosyltransferase and acyltransferase functions and is primarily associated with resistance against AMX [121]. A mutation in the PBP1A gene causes H. pylori to be resistant to the antibiotic AMX, as shown by Okamoto et al. [122]. Three crucial regions in the transpeptidase domain of PBP1A are STGK338–341, SKN402–404, and KTG555–557 [123]. Also, G591K and A480V in PBP1A are critical mutations linked to AMX resistance, as shown by Islam et al. [121] via the preparation and analysis of recombinants. Monique and her colleagues transferred these three fragments to cultures susceptible to AMX, and they discovered that transferring the last two fragments resulted in a moderate level of drug resistance in the sensitive strains. Changes in amino acids, specifically S402G (found in SKN402–404), E406A, S417T, S414R, T555S (found in KTG555–557), and N561Y, are what make H. pylori resistant [124]. Additionally, it was believed that low-molecular-weight PBPs were associated with H. pylori resistance [55]. For instance, PBPD, a PBP with a low molecular weight, is either absent or expressed at low levels in certain strains resistant to AMX [124].
16S rRNA
The RNA component of the 30S subunit of a bacterial ribosome is known as 16S ribosomal RNA, abbreviated as 16S rRNA. Forming the bulk of the SSU structure, it binds to the Shine-Dalgarno sequence [125]. Structure modeling and sequence analysis [126] show that the 16S rRNA gene sequence comprises many different and conserved regions. Point mutations in H. pylori's 16S rRNA impede TET attachment to the 16S ribosome's major binding site, a common TET resistance mechanism [127]. There is a high level of resistance to TET (MIC > 8 μg/mL) because there are three mutations (AGA965–967TTC) in the 16S rRNA sequence that are thought to bind TET. On the other hand, resistance at a low level (MIC ≤ 4 μg/mL) is caused by either double or single mutations [128]. Gerrits et al. [129] found a mutation (AGA926–928) in the 16S rRNA gene of H. pylori that made the minimum inhibitory concentration (MIC) of TET higher. Furthermore, they observed the A939C mutation in TET-resistant organisms that lacked AGA926-928 mutations. This indicates that other changes in the 16S rRNA gene are associated with TET resistance.
23S rRNA
Traditionally, in bacteria and archaea, the genes responsible for generating the RNA components of the ribosome are arranged inside a single operon in the 16S-23S-5S sequence.
The CLR inhibits bacteria's protein production by attaching to the peptidyl transferase ring in the V region of the 23S rRNA subunit [130]. This implies that changes in the 23S rRNA gene could provide CLR resistance [131]. Researchers have extensively explored the relationship between 23S rRNA mutations and resistance to CLR [132]. Mutations at A2142G, A2142C, and A2143G can provide high-level resistance to CLR [133, 134]. In contrast, CLR-resistant bacteria with lower CLR minimum inhibitory concentration (MIC) levels have unique point mutations, such as T2717C. The 23S rRNA also showed modifications such as A2115G, G2141A, A2144G, T2182C, and T2289C [135]. However, there is insufficient data to establish a link between these mutations and CLR resistance. Furthermore, it has been demonstrated that certain gene mutations have synergistic effects when combined with 23S rRNA changes. For example, it has been demonstrated that two mutations in genes other than 23S rRNA, namely rpl22 and infB, had synergistic effects when paired with mutations in the V region of 23S rRNA.
gyrA and gyrB
DNA gyrase is a tetrameric enzyme composed of two A and two B subunits encoded by the gyrA and gyrB genes [136]. Mutations in the quinolone resistance determination region (QRDR) of gyrA can alter the DNA helicase's interaction with quinolone antibiotics, resulting in LVX resistance [137, 138]. Changes in encoded amino acids caused by mutations in the gyrA gene have been shown to be concentrated in amino acids N87K, N87L, N87I, N87A, D91G, D91N, D91A, D91Y, and D91H [137, 139‐141]. Some gyrA mutations are complicated, involving other amino acid changes, such as D91N + L45F, D91Y + L45F, D91N + 130 K, D91G + A55S + G60S, and N87A + A88N + V65I [55]. A55S, D86N, A88P, A88V, R130K, and R295H are additional amino acid changes found in some H. pylori-resistant strains, indicating that H. pylori have other mutations linked to LVX resistance in addition to those that affect amino acids 87 and 91 [140, 141]. Furthermore, mutations in gyrB have been found in LVX-resistant strains, including E463K, S479G, D481E, and R484K, but their significance is unknown [43, 142, 143].
porD and oorD
Pyruvate-ferredoxin oxidoreductase POR is an enzyme that catalyzes the thiamine pyrophosphate (TPP)-dependent oxidative decarboxylation of pyruvate, resulting in acetyl-CoA and CO2 [144]. In contrast to pyruvate dehydrogenase, a widely distributed enzyme that catalyzes the same activity, POR can also catalyze the opposite reaction, namely the reductive carboxylation of acetyl-CoA, if a suitably low-potential electron donor is available [145]. POR is present in archaea, bacteria, and anaerobic protozoans. It belongs to the 2-oxoacid oxidoreductase (OR) family, catalyzes the oxidative decarboxylation of 2-oxoacids into acyl- or aryl-CoA derivatives [146]. The 2-oxoglutarate (-ketoglutarate) oxidoreductase (OOR) catalyzes the conversion of -ketoglutarate to succinyl-CoA and CO2 [146, 147]. The FR resistance mechanisms in H. pylori primarily stem from mutations in porD and oorD [55]. Su et al. [148], found G353A, A356G, and C357T changes in the porD genes of FR-resistant isolates. They also found A041G, A122G, and C349A(G) changes in the oorD gene. The six mutations in H. pylori's porD and oorD genes result in six amino acid alterations related to FR resistance [55]. Research is identifying more mutations as potentially associated with FR resistance, including C347T, C347G, and C346A in porD, and A78G, A112G, A335G, C156T, and C165T in oorD [149].
RdxA, frxA, and frxA
Mutations that inactivate the rdxA gene, which encodes an oxygen-insensitive NADPH nitroreductase, and/or the frxA gene, which encodes a NADPH: flavin oxidoreductase, are the primary causes of MNZ resistance. Subsequently, mutations in the fdxB gene, which encodes a ferredoxin-like protein, result from frameshift mutations, insertions, and deletions [150]. The rdxA activity significantly impacts nitroreductase activity, which is critical for MNZ antibiotic action [151]. Changes in the rdxA gene are the most important factor because they can make H. pylori resistant to MNZ without changing frxA. Studies have shown that frxA frameshift mutations happen simultaneously in resistant and sensitive strains [152]. As a result, frxA mutations are thought to facilitate rdxA-mediated MNZ resistance rather than give MNZ resistance in and of themselves [153]. A recent investigation discovered numerous significant changes in the rdxA gene of MNZ-resistant strains [154], whereas mutations in the fdxB gene are less common. Furthermore, fdxB disruption paired with an inactive rdxA gene increases MNZ resistance [155]. Alternative resistant strains are characterized by substituting different amino acids in their complete rdxA sequences [152]. Zhang et al. [151] sequenced the whole genome of 238 clinical H. pylori strains and found that only the R16H/C and M21A amino acid alterations in rdxA were significant contributors to MNZ resistance, while mutations in the other 15 locations were solely associated with H. pylori origin.
rpoB
The RFB, a semi-synthetic compound derived from rifamycin S (RFP), is predominantly employed to treat tuberculosis [156]. Rifamycinoid (RBU) exhibits superior efficacy against both Gram-positive and Gram-negative bacteria compared to RFP [157]. It stops transcription when RBU and other RFP compounds bind to the b-subunit of the DNA-dependent RNA polymerase (rpoB) [158]. Mutations in four distinct areas of the H. pylori rpoB gene may be responsible for the effects [159, 160]. The regions are named Cluster I (codons 525–545), Cluster II (codon 585), Codon 149, and Codon 701[161]. Prior studies have shown that resistant laboratory H. pylori mutations exclusively occur in cluster I and cluster II of the rpoB gene [159, 160]. These mutations are similar to those that cause resistance in Escherichia coli and Mycobacterium tuberculosis [162].
The substitution of codon 149 from GTC to TTC has been demonstrated to lead to significant resistance to RBU. On the other hand, various random mutations introduce different amino acids and result in varying resistance levels. The substitution of codon 701 from CGC to CAH frequently results in modest resistance [163]. In addition, another study discovered that most strains resistant to RFP have specific genetic abnormalities in the rpoB gene, which lead to alterations in codons 530, 540, and 545 [158]. These changes cause resistance to develop not only to RFP but also to RBU. Previous research has shown that three specific codons in this area—525 (L525I), 530 (D530G/D530E/D530V/D530N), and 540 (H540Y/H540N)—are the main places where mutations happen that make the bacteria very resistant [55]. Furthermore, strains exhibiting high resistance levels have observed other mutations, such as I586N and L547F [164].
Challenges, potential solutions, and future directions
At present, treatment-induced H. pylori elimination is beset by a number of obstacles [165]. Strategies for eradicating H. pylori have experienced significant changes since its discovery in 1983 [166]. The principal cause of this is the escalating incidence of antibiotic-resistant strains, which renders many medications ineffective within clinical environments [167]. Antibiotic resistance among multidrug-resistant microorganisms has been recognized as an additional barrier to clinical eradication therapy [168]. Furthermore, the progression towards antibiotic resistance in H. pylori is continuous and ever-changing.
The degree and characteristics of antibiotic resistance and sensitivity significantly influence the effectiveness of eradication therapy in clinical patients [169]. Consequently, regular modifications to antibiotic dosages are necessary in order to preserve their therapeutic effectiveness. Unfortunately, there is a scarcity of dependable epidemiological studies that consistently monitor the risk of antibiotic resistance among the local population in a number of regions [170]. This research must form the basis for the choice of empirical antimicrobial medications. Eradication therapy is less effective when patients disobey medical advice and adhere to atypical prescription regimens prescribed by specialists [171].
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There are a lot of factors that contribute to patients following their H. pylori eradication plans (Fig. 5). Several research and clinical practice advocate for multi-antibiotic, multi-pronged elimination regimens that regulate stomach pH [172]. Because of this intricacy, both the doctor and the patient face difficulties. The persistence of socioeconomic conditions, variations in medication accessibility, and disparities in the prevalence of H. pylori infection across regions remain impediments to developing effective treatment strategies for H. pylori eradication [173]. Drug susceptibility testing is essential in the battle against this pathogen, as an increasing number of patients are developing resistance to commonly prescribed medications, including the multidrug-resistant strain of H. pylori [174].
Fig. 5
Treatment strategies for antibiotic resistance to Helicobacter. Antibiotic susceptibility testing (AST) is vital for identifying bacterial resistance patterns and guiding antibiotic selection. This testing may be done using two methods: culture-based procedures like agar dilution and the E-test, or molecular techniques like Next-Generation Sequencing (NGS), Reverse Transcription PCR (Rt-PCR), and Droplet Digital PCR (ddPCR). Following the information gained by AST, numerous therapeutic strategies are investigated. Immunotherapy is critical in this situation, since it works by modifying immune system activity. This might include active immunotherapy approaches like vaccination, which boosts immune responses in cells and mucosal surfaces, resulting in the production of IgA antibodies that keep infections from sticking to and entering tissues. Immunotherapy, which includes the oral delivery of therapeutic antibodies such IgY and IgG, may help treat H. pylori in the stomach. CRISPR-Cas tools, such as CRISPR/Cas12a and CRISPR-Cas13a, which allow for precise gene editing to tackle antibiotic-resistant organisms. Furthermore, nanoparticle therapies should not be dismissed as a feasible option. Integrating these approaches marks a big step forward in precision medicine, aiding the battle against diseases that are more resistant to traditional treatments
Currently, antibiotic susceptibility testing (AST) technologies for H. pylori are largely classified as molecular-based and culture-based approaches [169, 175]. The agar dilution method, gradient diffusion susceptibility testing (E-test), broth microdilution method, and disc diffusion method are culture-based procedures that have historically been used as gold standards for H. pylori AST [176, 177]. These methods determine antibiotic sensitivity or resistance based on the antibiotic's minimum inhibitory concentration (MIC) under test [39, 169, 178].. Agar dilution is a reliable approach that can be used to test many H. pylori strains simultaneously and has been proposed as a reference assay for evaluating the correctness of other methods [178, 179]. The E-tests may quantify the disc diffusion technique and show a significant association with the agar dilution method for the majority of antibiotics, except for MNZ, which does not undergo anaerobic preincubation on the plates [180, 181]. In the regular clinical setting, the E-test outperforms agar dilution regarding cost and time [181].
Although culture-based approaches are presently the most successful for AST detection, they need stomach biopsy samples, which are only available via invasive endoscopic procedures. Furthermore, the technique is expensive, labor-intensive, and time-consuming, with results anticipated within one to two weeks since their dependability is heavily impacted by the samples given and the testing settings [182].
Molecular-based approaches work by identifying particular mutations in H. pylori that encode resistance mechanisms. They often provide advantages such as increased standardization and repeatability, quicker testing times (often resulting in findings the same day), and employing specimens collected using non-invasive procedures that do not need rapid processing [169]. Molecular-based approaches are classified into two main categories: next-generation sequencing (NGS) techniques and polymerase chain reaction (PCR)-based tests.
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There are numerous diagnostic methodologies, each of which has its advantages and disadvantages [165]. The selection of tests is contingent upon the hospital's medical requirements, the test availability, and the instruments available. There are numerous varieties of tests. Both invasive and noninvasive techniques can be employed to conduct diagnostic testing. Endoscopy, histopathological analyses, rapid urea tests, cultures, and PCR tests are examples of invasive techniques, while serological, stool antigen, and breath tests are examples of noninvasive strategies [165, 183]. PCR, real-time PCR, fluorescence in situ hybridization, and peptide mass fingerprinting are common molecular instruments employed in addition to invasive and noninvasive procedures. It is essential to have accurate diagnostic tests (DT) to maintain the quality of care by preventing the administration of ineffective therapies and/or excessive treatments [184]. In the context of infectious diseases, molecular DT has the potential to enhance the reliability of outcomes yielded by histology, microbiology culture, and monoclonal assays.
The PCR has a high sensitivity and specificity for detecting H. pylori in patients with chronic gastritis or nonpeptic ulcer hemorrhage, with a significant proportion of patients diagnosed with dyspepsia testing positive for H. pylori [185, 186]. PCR also identifies low-density infections in a significant proportion of patients with dyspepsia, unlike traditional methods. In a study of histologically negative gastritis, 49% of patients with persistent mucosal inflammation tested positive for H. pylori [187, 188]. PCR can identify active infection in healthy individuals previously ruled out for H. pylori using conventional testing methods [189, 190]. PCR can also help identify H. pylori in medical situations where a diagnosis is important but hard to obtain, such as peptic ulcer hemorrhage, gastric cancer, or MALT lymphoma [191]. This latter discovery also implies that low-density infections might be associated with more virulent strains and, as such, might not be harmless.
Digital PCR (dPCR) is the most recent advancement in PCR technology that is commercially available [192]. The dPCR is a quantitative technology that exhibits enhanced sensitivity compared to real-time or conventional PCR techniques without compromising specificity [193, 194]. dPCR serves as a valuable tool in identifying infectious agents across various sample types, particularly in identifying and genotyping resistance genes associated with H. pylori infection [195‐197]. Furthermore, researchers have used it to determine the significance of CYP219 polymorphisms in determining the efficacy of triple therapy [198]. Droplet digital PCR (ddPCR) is an approach that utilizes the production of water–oil emulsion particles to conduct dPCR [184]. ddPCR involves fractionating the PCR reaction of a single sample into 20,000 droplets, which are subsequently subjected to end-point PCR. Every droplet amplifies the template molecules, and a fluorescence detector determines the number of positive droplets.
A novel stool-based method for the detection, quantification, and partial genotyping of H. pylori was devised by Talarico et al. [199]. This method utilizes ddPCR, which enables absolute quantification and increased sensitivity through PCR partitioning. The stool-based ddPCR assays are a noninvasive, sensitive method for detecting, quantitating, and partially genotyping H. pylori. In comparison to serology and stool antigen tests, the stool-based H. pylori 16S ddPCR assay demonstrated a sensitivity of 84% and 100% and a specificity of 100% and 71% [199].
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Endoscopy with histology or culture, rapid urease testing (RUT), and molecular assays on clinical specimens are all established procedures for detecting H. pylori. Nevertheless, identifying H. pylori necessitates the development of a nucleic acid detection platform that is both precise and ultrasensitive [200].
The development of CRISPR-Cas13a-based antibacterial nucleocapsids, known as CapsidCas13a(s), that are capable of sequence-specifically targeting the microorganisms [201]. CRISPR-Cas13a-based antimicrobials have the potential to address the issue of antimicrobial-resistant organisms and may be employed to combat H. pylori resistance [202]. Wang et al. [203] validated and developed PCR-Cas13a as a promising method for the detection of H. pylori using the DNA of 84 clinical strains and 71 clinical specimens. This PCR-based CRISPR assay has a broad range of potential applications for detecting H. pylori and other slow-growing pathogens, as evidenced by their findings. While CapsidCas13a(s) has enormous potential for bacterial gene discovery [201], it does come with a few downsides, such as: (1) For each bacterial species and gene, a unique CapsidCas13a must be developed. (2) The data interpretation depends on the growth of bacteria, which may cause a delay in receiving the test results. (3) It becomes useless when the target gene cannot be translated or the bacteria cannot be cultured.
In contrast, Zhang et al. [204] developed a CRISPR/Cas12a-assisted array to screen for genotypes and detected H. pylori concentrations. This array can potentially be an effective tool for diagnosing and preventing H. pylori infection-related disorders and for large-scale clinical screening.
Curative strategies
Vaccination has emerged as a more viable approach to the clinical management of H. pylori infection, either to prevent infection or to treat an already established infection [165]. Vaccination is likely effective against drug-resistant strains and may potentially restrict the development of drug-resistant H. pylori [205]. As demonstrated in experimental models, immunization can also interrupt transmission and protect against reinfection. Although the prevalence of H. pylori infection in the developed world appears to be decreasing, estimates from a mathematical model suggest that eradicating H. pylori in the United States will take more than a century [165]. Indeed, a recent study evaluating the cost of H. pylori disease against the potential benefits of a vaccine suggests a highly favorable cost–benefit ratio [206].These changes impact the strength of the immunological and inflammatory responses of the host.
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Despite extensive study, there is currently no vaccine available for H. pylori infections. Several vaccine candidates have proceeded to early-stage clinical trials, but none have reached the market [207]. The bacterium's genetic diversity and the difficulties of eliciting a significant immune response provide challenges for the development of an effective H. pylori vaccine [208]. Especially, a recent bibliometric analysis noted that research on the H. pylori vaccine is currently under development and new antigen combinations are under investigated as viable prospects. These findings are currently being investigated; thus, no vaccine has completed the necessary clinical trials to be made public. As a result, although immunization against H. pylori remains a viable option for preventing infections and associated stomach diseases, it is critical to understand that no such vaccine is now available, and research is ongoing to address the existing challenges [165].
It is being looked into whether oral vaccinations against gastrointestinal pathogens like E. coli, V. cholerae, and H. pylori are better than injection-based vaccines because they are safer and boost immune responses at mucosal sites [209‐211]. However, administering vaccines orally is challenging due to unfavorable conditions in the gastrointestinal tract [211]. Currently, approved human oral vaccines primarily use attenuated viruses or pathogenic bacteria as carriers, which may regain their virulent properties. Lactic acid bacteria (LAB) have considerable promise as a carrier for oral vaccinations due to their generally recognized safe status, resistance to stomach acid, stability, and ability to activate both innate and adaptive immunity [212]. Research has focused on developing adjuvants and methods to administer oral immunizations, targeting M cells to ensure effectiveness. However, challenges remain, such as finding new ligands and methods for delivering immune responses to mucosal surfaces [213‐215]. On the other hand, passive vaccination with orally delivered anti-H. pylori antibodies may be an alternate therapy for H. pylori. Research has demonstrated the effectiveness of this technique in preventing and treating a wide range of infections, such as rotavirus, Candida albicans, Clostridium difficile, and Campylobacter jejuni [216].
Additionally, the oral delivery of therapeutic antibodies that directly neutralize bacterial infections, such as egg yolk immunoglobulin Y (IgY) [217] and bovine immunoglobulins (Igs) [218] Earlier research has shown that giving egg yolk IgY by mouth can help with passive immunization, which is crucial for stopping and treating bacterial, viral, and parasitic diseases in the gut [219]. As a result, the prospective benefits of employing egg yolk IgY specific to H. pylori in eradication may be worthwhile. Shin et al. [220] confirmed that egg yolk IgY against H. pylori whole-cell lysates inhibited H. pylori growth and the formation of inflammatory cells in Mongolian gerbils with H. pylori in their stomachs. More research by Suzuki et al. [221] showed that people who had H. pylori and were given anti-H. pylori urease IgY for four weeks had significantly lower C-urea breath test values than before treatment than before treatment. Recently, these subjects reported no serious side effects throughout the treatment period [222]. In a separate study, Borhani et al. [223] examined how well anti-H. pylori neutrophil-activating protein (NAP) IgY stopped H. pylori from sticking to stomach cancer cells. They discovered that anti-H. pylori NAP IgY may effectively inhibit H. pylori adherence to AGS cells. The data suggest that egg yolk IgY might be a viable option for preventing and treating H. pylori infection, especially in those who have established antibiotic resistance.
In contrast, bovine immunoglobulins (Igs) are responsible for preventing and treating numerous gastrointestinal infections, including H. pylori [218]. The Igs have been classified into three types: IgG, IgA, and IgM. Furthermore, IgG is classified into two subclasses: IgG1 and IgG2. The major function of immunoglobulins is to agglutinate bacteria, neutralize poisons, and inactivate viruses. IgA is capable of neutralizing viruses and bacterial toxins, as well as protecting against proteolysis. IgM outperforms other immunoglobulins in terms of complement fixation, viral neutralization, and bacterial agglutination. IgG may also tolerate gastric digestion. Numerous animal investigations have shown that bovine antibodies to H. pylori may prevent and even eliminate H. pylori infection by lowering the bacterial load [224, 225]. Breastfeeding protects babies from getting an early H. pylori infection in humans. This suggests that the passive delivery of immunoglobulin (Ig) A antibodies affects how H. pylori colonizes [226].
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The protective effect of hyperimmune bovine IgG was demonstrated for certain pathogens in vivo animal models, including H. pylori [218, 227, 228].In conclusion, Peypar et al. [229] comprehensive evaluations of 76 publications demonstrated that immunoglobulin Y is more efficient than bovine antibodies in treating H. pylori infection.
On the other hand, prior research has established the efficacy of metallic nanoparticles (NPs), such as those made of zinc, silver, H. pylori, or silver, in eradicating a wide variety of bacteria [230]. The phenomena above are ascribed to established mechanisms, which include nonoxidative stress, metal ion release, and oxidative stress [231]. A bactericidal effect can be attained through the use of NPs in deficient concentrations, thereby significantly impeding the capacity of bacteria to develop resistance [232]. AgNPs, specifically those obtained from biological sources such as algae, plants, fungi, and bacteria, possess distinct benefits compared to alternative metallic NPs [233, 234]. These advantages stem from the controlled particle size, shape, and monodispersity facilitated by their preparation methods, resulting in decreased preparation time. This is of particular significance when considering environmentally sustainable approaches prior.
Conclusion
Resistance of H. pylori to antibiotics is linked to various clinical complications. Among the bacterial factors contributing to H. pylori resistance are mutations, biofilms, coccoid form, and efflux pumps. H. pylori commonly employ gene modification strategies to circumvent bactericidal effects, specifically targeting genes associated with nucleic acid synthesis, rRNA coding, and cell wall formation. Biological activity and efflux pump systems are processes that are intricately intertwined. The initiation of efflux pump activation and concurrent biofilm formation, which leads to the development multidrug-resistant (MDR) bacteria, significantly complicates eradication therapy.
Finally, antibiotic susceptibility testing, various oral immunotherapy and vaccines, and the new technological tools used to manage H. pylori infection have been discussed.
Acknowledgements
This work was supported by the Researchers Supporting Project (RSPD2025R731), King Saud University (Riyadh, Saudi Arabia).
Declarations
Ethics approval and consent to participate
Not applicable.
Competing interests
The authors declare no competing interests.
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Antibiotic resistance in Helicobacter pylori: a genetic and physiological perspective
Verfasst von
Rania G. Elbaiomy
Xiaoling Luo
Rong Guo
Shiyuan Deng
Meifang Du
Ahmed H. El-Sappah
Mohammed Bakeer
Mahmoud M. Azzam
Ahmed A. Elolimy
Mahmoud Madkour
Zaixin Li
Zhi Zhang
Xu H, Yun J, Li R, Ma X, Gou L, Che T, Zhang D. Antibiotics resistance prevalence of Helicobacter pylori strains in Northwest China. Infect Drug Resist. 2022;15:5519–28.PubMedPubMedCentralCrossRef
3.
Hooi JK, Lai WY, Ng WK, Suen MM, Underwood FE, Tanyingoh D, Malfertheiner P, Graham DY, Wong VW, Wu JC. Global prevalence of Helicobacter pylori infection: systematic review and meta-analysis. Gastroenterology. 2017;153(2):420–9.PubMedCrossRef
4.
Keikha M, Sahebkar A, Yamaoka Y, Karbalaei M. Helicobacter pylori cagA status and gastric mucosa-associated lymphoid tissue lymphoma: a systematic review and meta-analysis. J Health Popul Nutr. 2022;41(1):2.PubMedPubMedCentralCrossRef
5.
Piscione M, Mazzone M, Di Marcantonio MC, Muraro R, Mincione G. Eradication of Helicobacter pylori and gastric cancer: a controversial relationship. Front Microbiol. 2021;12: 630852.PubMedPubMedCentralCrossRef
6.
Sugano K, Tack J, Kuipers EJ, Graham DY, El-Omar EM, Miura S, Haruma K, Asaka M, Uemura N, Malfertheiner P. Kyoto global consensus report on Helicobacter pylori gastritis. Gut. 2015;64(9):1353–67.PubMedCrossRef
7.
Stefano K, Marco M, Federica G, Laura B, Barbara B, Gioacchino L. Gian LdA: Helicobacter pylori, transmission routes and recurrence of infection: state of the art. Acta Bio Medica: Atenei Parmensis. 2018;89(Suppl 8):72.
8.
Schwarz S, Morelli G, Kusecek B, Manica A, Balloux F, Owen RJ, Graham DY, van der Merwe S, Achtman M, Suerbaum S. Horizontal versus familial transmission of Helicobacter pylori. PLoS Pathog. 2008;4(10): e1000180.PubMedPubMedCentralCrossRef
9.
Didelot X, Nell S, Yang I, Woltemate S, van der Merwe S, Suerbaum S. Genomic evolution and transmission of Helicobacter pylori in two South African families. Proc Natl Acad Sci USA. 2013;110(34):13880–5.PubMedPubMedCentralCrossRef
10.
Tshibangu-Kabamba E, Yamaoka Y. Helicobacter pylori infection and antibiotic resistance—from biology to clinical implications. Nat Rev Gastroenterol Hepatol. 2021;18(9):613–29.PubMedCrossRef
11.
King Z. Genomic characterisation and comparison of antibiotic resistant and sensitive Helicobacter pylori in New Zealand. Auckland, New Zealand: Auckland University of Technology; 2021.
12.
Chukwudi CU. rRNA binding sites and the molecular mechanism of action of the tetracyclines. Antimicrob Agents Chemother. 2016;60(8):4433–41.PubMedPubMedCentralCrossRef
13.
Addissouky TA, Wang Y, El Sayed IET, Baz AE, Ali MM, Khalil AA. Recent trends in Helicobacter pylori management: harnessing the power of AI and other advanced approaches. Beni-Suef Univer J Basic Appl Sci. 2023;12(1):80.CrossRef
14.
Graham DY, Fischbach L. Helicobacter pylori treatment in the era of increasing antibiotic resistance. Gut. 2010;59(8):1143–53.PubMedCrossRef
15.
Hasanuzzaman M, Bang CS, Gong EJ. Antibiotic resistance of Helicobacter pylori: mechanisms and clinical implications. J Korean Med Sci. 2024;39(4):e44.PubMedPubMedCentralCrossRef
16.
Savoldi A, Carrara E, Graham DY, Conti M, Tacconelli E. Prevalence of antibiotic resistance in Helicobacter pylori: a systematic review and meta-analysis in World Health Organization regions. Gastroenterology. 2018;155(5):1372–13821317.PubMedCrossRef
17.
Lin Y, Shao Y, Yan J, Ye G. Antibiotic resistance in Helicobacter pylori: from potential biomolecular mechanisms to clinical practice. J Clin Lab Anal. 2023;37(7): e24885.PubMedPubMedCentralCrossRef
18.
Rodis N, Tsapadikou V, Potsios C, Xaplanteri P. Resistance mechanisms in bacterial biofilm formations: a review. J Emerg Intern Med. 2020;4(1):8.
19.
Umar Z, Tang J-W, Marshall BJ, Tay ACY, Wang L. Rapid diagnosis and precision treatment of Helicobacter pylori infection in clinical settings. Crit Rev Microbiol. 2024;51:1–30.
20.
Liou JM, Malfertheiner P, Lee YC, Sheu BS, Sugano K, Cheng HC, Yeoh KG, Hsu PI, Goh KL, Mahachai V, et al. Screening and eradication of Helicobacter pylori for gastric cancer prevention: the Taipei global consensus. Gut. 2020;69(12):2093–112.PubMedCrossRef
21.
Borka Balas R, Meliț LE, Mărginean CO. Worldwide prevalence and risk factors of Helicobacter pylori infection in children. Children. 2022;9(9):1359.PubMedPubMedCentralCrossRef
22.
Li Y, Choi H, Leung K, Jiang F, Graham DY, Leung WK. Global prevalence of Helicobacter pylori infection between 1980 and 2022: a systematic review and meta-analysis. Lancet Gastroenterol hepatol. 2023;8(6):553–64.PubMedCrossRef
23.
Chen Y-C, Malfertheiner P, Yu H-T, Kuo C-L, Chang Y-Y, Meng F-T, Wu Y-X, Hsiao J-L, Chen M-J, Lin K-P. Global prevalence of Helicobacter pylori infection and incidence of gastric cancer between 1980 and 2022. Gastroenterology. 2024;166(4):605–19.PubMedCrossRef
24.
Saxena A, Mukhopadhyay AK, Nandi SP. Helicobacter pylori: perturbation and restoration of gut microbiome. J Biosci. 2020;45:1–15.CrossRef
25.
Yuan C, Adeloye D, Luk TT, Huang L, He Y, Xu Y, Ye X, Yi Q, Song P, Rudan I. The global prevalence of and factors associated with Helicobacter pylori infection in children: a systematic review and meta-analysis. Lancet Child Adolescent Health. 2022;6:185–94.PubMedCrossRef
26.
Malfertheiner P, Megraud F, Rokkas T, Gisbert JP, Liou J-M, Schulz C, Gasbarrini A, Hunt RH, Leja M, O’Morain C. Management of Helicobacter pylori infection: the Maastricht VI/Florence consensus report. Gut. 2022;71(9):1724–62.CrossRef
27.
Jung HK, Kang SJ, Lee YC, Yang HJ, Park SY, Shin CM, Kim SE, Lim HC, Kim JH, Nam SY, et al. Evidence-based guidelines for the treatment of Helicobacter pylori Infection in Korea 2020. Gut Liver. 2021;15(2):168–95.PubMedPubMedCentralCrossRef
28.
Thung I, Aramin H, Vavinskaya V, Gupta S, Park J, Crowe S, Valasek M. the global emergence of Helicobacter pylori antibiotic resistance. Aliment Pharmacol Ther. 2016;43(4):514–33.PubMedCrossRef
29.
Lee JW, Kim N, Choi SI, Jang JY, Song CH, Nam RH, Lee DH. Prevalence and trends of multiple antimicrobial resistance of Helicobacter pylori in one tertiary hospital for 20 years in Korea. Helicobacter. 2023;28(1): e12939.PubMedCrossRef
30.
Ho JJC, Navarro M, Sawyer K, Elfanagely Y, Moss SF. Helicobacter pylori Antibiotic Resistance in the United States Between 2011 and 2021: a systematic review and meta-analysis. Am J Gastroenterol. 2022;117(8):1221–30.PubMedCrossRef
31.
Suerbaum S, Michetti P. Helicobacter pylori infection. N Engl J Med. 2002;347(15):1175–86.PubMedCrossRef
32.
Camorlinga-Ponce M, Gómez-Delgado A, Aguilar-Zamora E, Torres RC, Giono-Cerezo S, Escobar-Ogaz A, Torres J. Phenotypic and genotypic antibiotic resistance patterns in Helicobacter pylori strains from ethnically diverse population in México. Front Cell Infect Microbiol. 2021;10:539115.PubMedPubMedCentralCrossRef
33.
Nguyen KV, Thi Do NT, Chandna A, Nguyen TV, Pham CV, Doan PM, Nguyen AQ, Thi Nguyen CK, Larsson M, Escalante S. Antibiotic use and resistance in emerging economies: a situation analysis for Viet Nam. BMC Public Health. 2013;13:1–10.CrossRef
34.
Kasahun GG, Demoz GT, Desta DM. Primary resistance pattern of Helicobacter pylori to antibiotics in adult population: a systematic review. Infect Drug Resist. 2020;13:1567–73.PubMedPubMedCentralCrossRef
35.
Ballal M. Trends in antimicrobial resistance among enteric pathogens: a global concern. Antibiotic Resis. 2016;63:3S-8S.
36.
Mölter A, Belmonte M, Palin V, Mistry C, Sperrin M, White A, Welfare W, Van Staa T. Antibiotic prescribing patterns in general medical practices in England: does area matter? Health Place. 2018;53:10–6.PubMedCrossRef
37.
Schwartz KL, Morris SK. Travel and the spread of drug-resistant bacteria. Current Infect Dis Rep. 2018;20:1–10.CrossRef
38.
Loftus MJ, Stewardson AJ, Naidu R, Coghlan B, Jenney AW, Kepas J, Lavu E, Munamua AB, Peel TN, Sahai V. Antimicrobial resistance in the Pacific Island countries and territories. BMJ Glob Health. 2020;5(4): e002418.PubMedPubMedCentralCrossRef
39.
Gerrits MM, van Vliet AH, Kuipers EJ, Kusters JG. Helicobacter pylori and antimicrobial resistance: molecular mechanisms and clinical implications. Lancet Infect Dis. 2006;6(11):699–709.PubMedCrossRef
40.
Sharma P, Hu-Lieskovan S, Wargo JA, Ribas A. Primary, adaptive, and acquired resistance to cancer immunotherapy. Cell. 2017;168(4):707–23.PubMedPubMedCentralCrossRef
41.
Zilahi G, Artigas A, Martin-Loeches I. What’s new in multidrug-resistant pathogens in the ICU? Ann Intensive Care. 2016;6:1–11.CrossRef
42.
Andersson DI, Balaban NQ, Baquero F, Courvalin P, Glaser P, Gophna U, Kishony R, Molin S, Tønjum T. Antibiotic resistance: turning evolutionary principles into clinical reality. FEMS Microbiol Rev. 2020;44(2):171–88.PubMedCrossRef
43.
López-Gasca M, Peña J, García-Amado MA, Michelangeli F, Contreras M. Point Mutations at gyrA and gyrB Genes of Levofloxacin-Resistant Helicobacter pylori Isolates in the Esophageal Mucosa from a Venezuelan Population. Am J Trop Med Hyg. 2018;98(4):1051–5.PubMedPubMedCentralCrossRef
44.
Gaurav A, Bakht P, Saini M, Pandey S, Pathania R. Role of bacterial efflux pumps in antibiotic resistance, virulence, and strategies to discover novel efflux pump inhibitors. Microbiology. 2023;169(5):001333.PubMedPubMedCentralCrossRef
45.
Ma D, Cook D, Alberti M, Pon N, Nikaido H, Hearst J. Molecular cloning and characterization of acrA and acrE genes of Escherichia coli. J Bacteriol. 1993;175(19):6299–313.PubMedPubMedCentralCrossRef
46.
Li X-Z, Livermore DM, Nikaido H. Role of efflux pump (s) in intrinsic resistance of Pseudomonas aeruginosa: resistance to tetracycline, chloramphenicol, and norfloxacin. Antimicrob Agents Chemother. 1994;38(8):1732–41.PubMedPubMedCentralCrossRef
47.
Li XZ, Plésiat P, Nikaido H. The challenge of efflux-mediated antibiotic resistance in Gram-negative bacteria. Clin Microbiol Rev. 2015;28(2):337–418.PubMedPubMedCentralCrossRef
48.
van Amsterdam K, Bart A, van der Ende A. A Helicobacter pylori TolC efflux pump confers resistance to metronidazole. Antimicrob Agents Chemother. 2005;49(4):1477–82.PubMedPubMedCentralCrossRef
49.
Blair JM, Richmond GE, Piddock LJ. Multidrug efflux pumps in Gram-negative bacteria and their role in antibiotic resistance. Future Microbiol. 2014;9(10):1165–77.PubMedCrossRef
50.
Sharma A, Gupta VK, Pathania R. Efflux pump inhibitors for bacterial pathogens: from bench to bedside. Indian J Med Res. 2019;149(2):129–45.PubMedPubMedCentralCrossRef
51.
Chung YJ, Saier M Jr. SMR-type multidrug resistance pumps. Curr Opin Drug Discov Devel. 2001;4(2):237–45.PubMed
52.
Schneider E, Hunke S. ATP-binding-cassette (ABC) transport systems: functional and structural aspects of the ATP-hydrolyzing subunits/domains. FEMS Microbiol Rev. 1998;22(1):1–20.PubMedCrossRef
53.
Falsafi T, Ehsani A, Attaran B, Niknam V. Association of hp1181 and hp1184 genes with the active efflux phenotype in multidrug-resistant isolates of Helicobacter pylori. Jundishapur J Microbiol. 2016;9(4):e30726.PubMedPubMedCentralCrossRef
54.
Raj DS, Kesavan DK, Muthusamy N, Umamaheswari S. Efflux pumps potential drug targets to circumvent drug Resistance-Multi drug efflux pumps of Helicobacter pylori. Mater Today Proceed. 2021;45:2976–81.CrossRef
55.
Lin Y, Shao Y, Yan J, Ye G. Antibiotic resistance in Helicobacter pylori: From potential biomolecular mechanisms to clinical practice. J Clin Laborat Analys. 2023;37:e24885.CrossRef
56.
Wroblewski LE, Peek RM Jr, Wilson KT. Helicobacter pylori and gastric cancer: factors that modulate disease risk. Clin Microbiol Rev. 2010;23(4):713–39.PubMedPubMedCentralCrossRef
Ge X, Cai Y, Chen Z, Gao S, Geng X, Li Y, Li Y, Jia J, Sun Y. Bifunctional enzyme SpoT Is involved in biofilm formation of Helicobacter pylori with multidrug resistance by upregulating efflux pump Hp1174 (gluP). Antimicrob Agents Chemotherapy. 2018. https://doi.org/10.1128/aac.00957-00918.CrossRef
59.
Reygaert WC. An overview of the antimicrobial resistance mechanisms of bacteria. AIMS Microbiol. 2018;4(3):482.PubMedPubMedCentralCrossRef
60.
Piddock LJV. Multidrug-resistance efflux pumps ? not just for resistance. Nat Rev Microbiol. 2006;4(8):629–36.PubMedCrossRef
Ahmad I, Ali M, Ali R, Nawaz N, Patching SG. Multidrug efflux protein families in bacteria: ABC, RND, MFS, SMR, MATE, PACE, AbgT (An Update). Biochemistry. 2024;40:1–32.
63.
Koehn LM: ABC transporters: an overview. The ADME encyclopedia: a comprehensive guide on biopharmacy and pharmacokinetics 2022
64.
Zanotti G, Cendron L. Structural and functional aspects of the Helicobacter pylori secretome. World J Gastroenterol: WJG. 2014;20(6):1402.PubMedPubMedCentralCrossRef
65.
Sun J, Deng Z, Yan A. Bacterial multidrug efflux pumps: mechanisms, physiology and pharmacological exploitations. Biochem Biophys Res Commun. 2014;453(2):254–67.PubMedCrossRef
66.
De Kievit TR, Parkins MD, Gillis RJ, Srikumar R, Ceri H, Poole K, Iglewski BH, Storey DG. Multidrug efflux pumps: expression patterns and contribution to antibiotic resistance in Pseudomonas aeruginosa biofilms. Antimicrob Agents Chemother. 2001;45(6):1761–70.PubMedPubMedCentralCrossRef
67.
Yamasaki S, Wang LiYuan WL, Hirata T, Hayashi-Nishino M, Nishino K: Multidrug efflux pumps contribute to Escherichia coli biofilm maintenance. 2015.
68.
Soto SM. Role of efflux pumps in the antibiotic resistance of bacteria embedded in a biofilm. Virulence. 2013;4(3):223–9.PubMedPubMedCentralCrossRef
69.
Yonezawa H, Osaki T, Hanawa T, Kurata S, Ochiai K, Kamiya S. Impact of Helicobacter pylori biofilm formation on clarithromycin susceptibility and generation of resistance mutations. PLoS ONE. 2013;8(9): e73301.PubMedPubMedCentralCrossRef
70.
Tomb J-F, White O, Kerlavage AR, Clayton RA, Sutton GG, Fleischmann RD, Ketchum KA, Klenk HP, Gill S, Dougherty BA. The complete genome sequence of the gastric pathogen Helicobacter pylori. Nature. 1997;388(6642):539–47.PubMedCrossRef
71.
Gong X, Wang Y, An Y, Li Z, Liu D, Yong X. The crosstalk between efflux pump and resistance gene mutation in Helicobacter pylori. Gut microbes. 2024;16(1):2379439.PubMedPubMedCentralCrossRef
72.
Alfaray RI, Saruuljavkhlan B, Fauzia KA, Torres RC, Thorell K, Dewi SR, Kryukov KA, Matsumoto T, Akada J. Vilaichone R-k: Global antimicrobial resistance gene study of Helicobacter pylori: comparison of detection tools, ARG and efflux pump gene analysis, worldwide epidemiological distribution, and information related to the antimicrobial-resistant phenotype. Antibiotics. 2023;12(7):1118.PubMedPubMedCentralCrossRef
73.
Krzyżek P, Migdał P, Grande R, Gościniak G. Biofilm formation of Helicobacter pylori in both static and microfluidic conditions is associated with resistance to clarithromycin. Front Cell Infect Microbiol. 2022;12: 868905.PubMedPubMedCentralCrossRef
74.
Guzmán-Soto I, McTiernan C, Gonzalez-Gomez M, Ross A, Gupta K, Suuronen EJ, Mah TF, Griffith M, Alarcon EI. Mimicking biofilm formation and development: recent progress in in vitro and in vivo biofilm models. iScience. 2021;24(5):102443.PubMedPubMedCentralCrossRef
75.
Bowler P, Murphy C, Wolcott R. Biofilm exacerbates antibiotic resistance: Is this a current oversight in antimicrobial stewardship? Antimicrob Resist Infect Control. 2020;9(1):1–5.CrossRef
76.
Penesyan A, Paulsen IT, Kjelleberg S, Gillings MR. Three faces of biofilms: a microbial lifestyle, a nascent multicellular organism, and an incubator for diversity. Npj Biofilms Microbiom. 2021;7(1):80.CrossRef
77.
Flemming H-C, Baveye P, Neu TR, Stoodley P, Szewzyk U, Wingender J, Wuertz S. Who put the film in biofilm? The migration of a term from wastewater engineering to medicine and beyond. Npj Biofilms Microbiom. 2021;7(1):10.CrossRef
78.
Jamal M, Ahmad W, Andleeb S, Jalil F, Imran M, Nawaz MA, Hussain T, Ali M, Rafiq M, Kamil MA. Bacterial biofilm and associated infections. J Chin Med Associat. 2018;81(1):7–11.CrossRef
Hall CW, Mah TF. Molecular mechanisms of biofilm-based antibiotic resistance and tolerance in pathogenic bacteria. FEMS Microbiol Rev. 2017;41(3):276–301.PubMedCrossRef
81.
Khan J, Tarar SM, Gul I, Nawaz U, Arshad M. Challenges of antibiotic resistance biofilms and potential combating strategies: a review. 3 Biotech. 2021;11(4):169.PubMedPubMedCentralCrossRef
82.
Singh A, Amod A, Pandey P, Bose P, Pingali MS, Shivalkar S, Varadwaj PK, Sahoo AK, Samanta SK. Bacterial biofilm infections, their resistance to antibiotics therapy and current treatment strategies. Biomed Mater. 2022;17(2):022003.CrossRef
83.
Pozzi C, Waters EM, Rudkin JK, Schaeffer CR, Lohan AJ, Tong P, Loftus BJ, Pier GB, Fey PD, Massey RC, et al. Methicillin resistance alters the biofilm phenotype and attenuates virulence in Staphylococcus aureus device-associated infections. PLoS Pathog. 2012;8(4): e1002626.PubMedPubMedCentralCrossRef
84.
Dominguez EG, Zarnowski R, Choy HL, Zhao M, Sanchez H, Nett JE, Andes DR. Conserved role for biofilm matrix polysaccharides in candida auris drug resistance. Sphere. 2019;4(1):10–128.
85.
Neupane S, Pant ND, Khatiwada S, Chaudhary R, Banjara MR. Correlation between biofilm formation and resistance toward different commonly used antibiotics along with extended spectrum beta lactamase production in uropathogenic Escherichia coli isolated from the patients suspected of urinary tract infections visiting Shree Birendra Hospital, Chhauni, Kathmandu. Nepal Antimicrobial Resist Infect Control. 2016;5:5.CrossRef
86.
Senobar Tahaei SA, Stájer A, Barrak I, Ostorházi E, Szabó D, Gajdács M. Correlation between biofilm-formation and the antibiotic resistant phenotype in Staphylococcus aureus isolates: a laboratory-based study in hungary and a review of the literature. Infect Drug Resist. 2021;14:1155–68.PubMedPubMedCentralCrossRef
87.
Saber T, Samir M, El-Mekkawy RM, Ariny E, El-Sayed SR, Enan G, Abdelatif SH, Askora A, Merwad AMA, Tartor YH. Methicillin- and vancomycin-resistant Staphylococcus aureus from humans and ready-to-eat meat: characterization of antimicrobial resistance and biofilm formation ability. Front Microbiol. 2021;12: 735494.PubMedCrossRef
88.
Bardbari AM, Arabestani MR, Karami M, Keramat F, Alikhani MY, Bagheri KP. Correlation between ability of biofilm formation with their responsible genes and MDR patterns in clinical and environmental Acinetobacter baumannii isolates. Microb Pathog. 2017;108:122–8.PubMedCrossRef
89.
Belbase A, Pant ND, Nepal K, Neupane B, Baidhya R, Baidya R, Lekhak B. Antibiotic resistance and biofilm production among the strains of Staphylococcus aureus isolated from pus/wound swab samples in a tertiary care hospital in Nepal. Ann Clin Microbiol Antimicrob. 2017;16(1):15.PubMedPubMedCentralCrossRef
90.
El-Zamkan MA, Mohamed HMA. Antimicrobial resistance, virulence genes and biofilm formation in Enterococcus species isolated from milk of sheep and goat with subclinical mastitis. PLoS ONE. 2021;16(11): e0259584.PubMedPubMedCentralCrossRef
91.
Ratajczak M, Kamińska D, Nowak-Malczewska DM, Schneider A, Dlugaszewska J. Relationship between antibiotic resistance, biofilm formation, genes coding virulence factors and source of origin of Pseudomonas aeruginosa clinical strains. Annals Agric Environ Med. 2021;28(2):306–13.CrossRef
92.
Hathroubi S, Servetas SL, Windham I, Merrell DS, Ottemann KM. Helicobacter pylori biofilm formation and its potential role in pathogenesis. Microbio Mol Bio Rev. 2018. https://doi.org/10.1128/mmbr.00001-00018.CrossRef
93.
Macfarlane S, Dillon JF. Microbial biofilms in the human gastrointestinal tract. J Appl Microbiol. 2007;102(5):1187–96.PubMedCrossRef
94.
Motta JP, Wallace JL, Buret AG, Deraison C, Vergnolle N. Gastrointestinal biofilms in health and disease. Nat Rev Gastroenterol Hepatol. 2021;18(5):314–34.PubMedCrossRef
95.
Krzyżek P, Grande R, Migdał P, Paluch E, Gościniak G. Biofilm formation as a complex result of virulence and adaptive responses of Helicobacter pylori. Pathogens. 2020;9(12):1062.PubMedPubMedCentralCrossRef
96.
Attaran B, Falsafi T, Ghorbanmehr N. Effect of biofilm formation by clinical isolates of Helicobacter pylori on the efflux-mediated resistance to commonly used antibiotics. World J Gastroenterol. 2017;23(7):1163–70.PubMedPubMedCentralCrossRef
97.
Yonezawa H, Osaki T, Hojo F, Kamiya S. Effect of Helicobacter pylori biofilm formation on susceptibility to amoxicillin, metronidazole and clarithromycin. Microb Pathog. 2019;132:100–8.PubMedCrossRef
98.
Cai Y, Wang C, Chen Z, Xu Z, Li H, Li W, Sun Y. Transporters HP0939, HP0497, and HP0471 participate in intrinsic multidrug resistance and biofilm formation in Helicobacter pylori by enhancing drug efflux. Helicobacter. 2020;25(4): e12715.PubMedCrossRef
99.
Fauzia KA, Miftahussurur M, Syam AF, Waskito LA, Doohan D, Rezkitha YAA, Matsumoto T, Tuan VP, Akada J, Yonezawa H, et al. Biofilm formation and antibiotic resistance phenotype of Helicobacter pylori clinical isolates. Toxins. 2020;12(8):473.PubMedPubMedCentralCrossRef
100.
Windham IH, Servetas SL, Whitmire JM, Pletzer D, Hancock RE, Merrell DS. Helicobacter pylori biofilm formation is differentially affected by common culture conditions, and proteins play a central role in the biofilm matrix. Appl Environ Microbiol. 2018;84(14):e00391-e1318.PubMedPubMedCentralCrossRef
Krzyżek P, Migdał P, Tusiewicz K, Zawadzki M, Szpot P. Subinhibitory concentrations of antibiotics affect development and parameters of Helicobacter pylori biofilm. Front Pharmacol. 2024;15:1477317.PubMedPubMedCentralCrossRef
103.
Andersen LP, Rasmussen L. Helicobacter pylori-coccoid forms and biofilm formation. FEMS Immunol Med Microbiol. 2009;56(2):112–5.PubMedCrossRef
104.
Nilius M, Ströhle A, Bode G, Malfertheiner P. Coccoid like forms (CLF) of Helicobacter pylori Enzyme activity and antigenicity. Zentralblatt fur Bakteriologie. 1993;280(12):259–72.PubMedCrossRef
105.
Benaissa M, Babin P, Quellard N, Pezennec L, Cenatiempo Y, Fauchère JL. Changes in Helicobacter pylori ultrastructure and antigens during conversion from the bacillary to the coccoid form. Infect Immun. 1996;64(6):2331–5.PubMedPubMedCentralCrossRef
106.
Saito N, Konishi K, Sato F, Kato M, Takeda H, Sugiyama T, Asaka M. Plural transformation-processes from spiral to coccoid Helicobacter pylori and its viability. J Infect. 2003;46(1):49–55.PubMedCrossRef
107.
Krzyżek P, Biernat MM, Gościniak G. Intensive formation of coccoid forms as a feature strongly associated with highly pathogenic Helicobacter pylori strains. Folia Microbiol. 2019;64(3):273–81.CrossRef
108.
West AP, Millar MR, Tompkins DS. Effect of physical environment on survival of Helicobacter pylori. J Clin Pathol. 1992;45(3):228–31.PubMedPubMedCentralCrossRef
109.
Shahamat M, Paszko-Kolva C, Yamamoto H, Colwell R. Ecological studies of Campylobacter pylori. Klin Wochenschr. 1989;67(Suppl XVII):62–3.
110.
Konishi K, Saito N, Shoji E, Takeda H, Kato M, Asaka M. OOI HK: Helicobacter pylori: longer survival in deep ground water and sea water than in a nutrient-rich environment. APMIS. 2007;115(11):1285–91.PubMedCrossRef
111.
Berry V, Jennings K, Woodnutt G. Bactericidal and morphological effects of amoxicillin on Helicobacter pylori. Antimicrob Agents Chemother. 1995;39(8):1859–61.PubMedPubMedCentralCrossRef
112.
Sisto F, Brenciaglia M, Scaltrito M, Dubini F. Helicobacter pylori: ureA, cagA and vacA expression during conversion to the coccoid form. Int J Antimicrob Agents. 2000;15(4):277–82.PubMedCrossRef
113.
Bode G, Mauch F, Malfertheiner P. The coccoid forms of Helicobacter pylori Criteria for their viability. Epidemiol Infect. 1993;111(3):483–90.PubMedPubMedCentralCrossRef
114.
DeLoney CR, Schiller NL. Competition of various β-lactam antibiotics for the major penicillin-binding proteins of Helicobacter pylori: antibacterial activity and effects on bacterial morphology. Antimicrob Agents Chemother. 1999;43(11):2702–9.PubMedPubMedCentralCrossRef
115.
Citterio B, Casaroli A, Pierfelici L, Battistelli M, Falcieri E, Baffone W. Morphological changes and outer membrane protein patterns in Helicobacter pylori during conversion from bacillary to coccoid form. New Microbiol. 2004;27(4):353–60.PubMed
116.
She F-F, Su D-H, Lin J-Y, Zhou L-Y. Virulence and potential pathogenicity of coccoid Helicobacter pylori induced by antibiotics. World J Gastroenterol. 2001;7(2):254.PubMedPubMedCentralCrossRef
117.
Liu Y, Wang S, Yang F, Chi W, Ding L, Liu T, Zhu F, Ji D, Zhou J, Fang Y. Antimicrobial resistance patterns and genetic elements associated with the antibiotic resistance of Helicobacter pylori strains from Shanghai. Gut pathogens. 2022;14(1):14.PubMedPubMedCentralCrossRef
118.
Macheboeuf P, Di Guilmi AM, Job V, Vernet T, Dideberg O, Dessen A. Active site restructuring regulates ligand recognition in class A penicillin-binding proteins. Proc Natl Acad Sci USA. 2005;102(3):577–82.PubMedPubMedCentralCrossRef
119.
Straume D, Piechowiak KW, Kjos M, Håvarstein LS. Class A PBPs: It is time to rethink traditional paradigms. Mol Microbiol. 2021;116(1):41–52.PubMedCrossRef
120.
Popham DL, Young KD. Role of penicillin-binding proteins in bacterial cell morphogenesis. Curr Opin Microbiol. 2003;6(6):594–9.PubMedCrossRef
121.
Islam JM, Yano Y, Okamoto A, Matsuda R, Shiraishi M, Hashimoto Y, Morita N, Takeuchi H, Suganuma N, Takeuchi H. Evidence of Helicobacter pylori heterogeneity in human stomachs by susceptibility testing and characterization of mutations in drug-resistant isolates. Sci Rep. 2024;14(1):12066.PubMedPubMedCentralCrossRef
122.
Okamoto T, Yoshiyama H, Nakazawa T, Park I-D, Chang M-W, Yanai H, Okita K, Shirai M. A change in PBP1 is involved in amoxicillin resistance of clinical isolates of Helicobacter pylori. J Antimicrob Chemother. 2002;50(6):849–56.PubMedCrossRef
123.
Gerrits MM, Godoy AP, Kuipers EJ, Ribeiro ML, Stoof J, Mendonça S, Van Vliet AH, Pedrazzoli J Jr, Kusters JG. Multiple mutations in or adjacent to the conserved penicillin-binding protein motifs of the penicillin-binding protein 1A confer amoxicillin resistance to Helicobacter pylori. Helicobacter. 2006;11(3):181–7.PubMedCrossRef
124.
Rimbara E, Noguchi N, Kawai T, Sasatsu M. Mutations in penicillin-binding proteins 1, 2 and 3 are responsible for amoxicillin resistance in Helicobacter pylori. J Antimicrob Chemother. 2008;61(5):995–8.PubMedCrossRef
125.
Alberts B: Molecular biology of the cell: Garland science; 2017.
126.
Johnson JS, Spakowicz DJ, Hong B-Y, Petersen LM, Demkowicz P, Chen L, Leopold SR, Hanson BM, Agresta HO, Gerstein M, et al. Evaluation of 16S rRNA gene sequencing for species and strain-level microbiome analysis. Nat Commun. 2019;10(1):5029.PubMedPubMedCentralCrossRef
127.
Dailidiene D, Bertoli MT, Miciuleviciene J, Mukhopadhyay AK, Dailide G, Pascasio MA, Kupcinskas L, Berg DE. Emergence of tetracycline resistance in Helicobacter pylori: multiple mutational changes in 16S ribosomal DNA and other genetic loci. Antimicrob Agents Chemother. 2002;46(12):3940–6.PubMedPubMedCentralCrossRef
128.
Trieber CA, Taylor DE. Mutations in the 16S rRNA genes of Helicobacter pylori mediate resistance to tetracycline. J Bacteriol. 2002;184(8):2131–40.PubMedPubMedCentralCrossRef
129.
Gerrits MM, de Zoete MR, Arents NL, Kuipers EJ, Kusters JG. 16S rRNA mutation-mediated tetracycline resistance in Helicobacter pylori. Antimicrob Agents Chemother. 2002;46(9):2996–3000.PubMedPubMedCentralCrossRef
130.
Vester B, Douthwaite S. Macrolide resistance conferred by base substitutions in 23S rRNA. Antimicrob Agents Chemother. 2001;45(1):1–12.PubMedPubMedCentralCrossRef
131.
Alkharsah KR, Aljindan RY, Alamri AM, Alomar AI, Al-Quorain AA. Molecular characterization of Helicobacter pylori clinical isolates from Eastern Saudi Arabia. Saudi Med J. 2022;43(10):1128–35.PubMedPubMedCentralCrossRef
132.
Liu Z, Shen J, Zhang L, Shen L, Li Q, Zhang B, Zhou J, Gu L, Feng G, Ma J, et al. Prevalence of A2143G mutation of H pylori-23S rRNA in Chinese subjects with and without clarithromycin use history. BMC Microbio. 2008;8:81.CrossRef
133.
van der Ende A, van Doorn LJ, Rooijakkers S, Feller M, Tytgat GN, Dankert J. Clarithromycin-susceptible and -resistant Helicobacter pylori isolates with identical randomly amplified polymorphic DNA-PCR genotypes cultured from single gastric biopsy specimens prior to antibiotic therapy. J Clin Microbiol. 2001;39(7):2648–51.PubMedPubMedCentralCrossRef
134.
Noh JH, Ahn JY, Choi J, Park YS, Na HK, Lee JH, Jung KW, Kim DH, Choi KD, Song HJ, et al. Real-time polymerase chain reaction for the detection of Helicobacter pylori and clarithromycin resistance. Gut Liver. 2023;17(3):375–81.PubMedCrossRef
135.
Abd albagi SO, aldayem Altayeb HN, Khalil Abuzeid NM: Molecular detection and characterization of mutation on 23S rRNA gene associated with clarithromycin resistant in Helicobacter pylori. bioRxiv 2019:650432.
136.
El-Badawy MF, Eed EM, Sleem AS, El-Sheikh AAK, Maghrabi IA, Abdelwahab SF. The first Saudi report of novel and common mutations in the gyrA and parC genes among Pseudomonas Spp. Clinical isolates recovered from Taif area. Infection Drug Resist. 2022;15:3801–14.CrossRef
137.
Garcia M, Raymond J, Garnier M, Cremniter J, Burucoa C. Distribution of spontaneous gyrA mutations in 97 fluoroquinolone-resistant Helicobacter pylori isolates collected in France. Antimicrob Agents Chemother. 2012;56(1):550–1.PubMedPubMedCentralCrossRef
138.
Thapa J, Chizimu JY, Kitamura S, Akapelwa ML, Suwanthada P, Miura N, Toyting J, Nishimura T, Hasegawa N, Nishiuchi Y, et al. Characterization of DNA gyrase activity and elucidation of the impact of amino acid substitution in GyrA on fluoroquinolone resistance in Mycobacterium avium. Microbiology spectrum. 2023;11(3): e0508822.PubMedCrossRef
139.
Shetty V, Lamichhane B, Tay CY, Pai GC, Lingadakai R, Balaraju G, Shetty S, Ballal M, Chua EG. High primary resistance to metronidazole and levofloxacin, and a moderate resistance to clarithromycin in Helicobacter pylori isolated from Karnataka patients. Gut pathogens. 2019;11(1):1–8.CrossRef
140.
Phan TN, Santona A, Tran TNH, Cappuccinelli P, Rubino S, Paglietti B. High rate of levofloxacin resistance in a background of clarithromycin-and metronidazole-resistant Helicobacter pylori in Vietnam. Int J Antimicrob Agents. 2015;45(3):244–8.PubMedCrossRef
141.
Cattoir V, Nectoux J, Lascols C, Deforges L, Delchier J-C, Megraud F, Soussy C-J, Cambau E. Update on fluoroquinolone resistance in Helicobacter pylori: new mutations leading to resistance and first description of a gyrA polymorphism associated with hypersusceptibility. Int J Antimicrob Agents. 2007;29(4):389–96.PubMedCrossRef
142.
Puah SM, Goh KL, Ng HK, Chua KH. Current status of Helicobacter pylori resistance to Clarithromycin and Levofloxacin in Malaysia-findings from a molecular based study. PeerJ. 2021;9: e11518.PubMedPubMedCentralCrossRef
143.
Rimbara E, Noguchi N, Kawai T, Sasatsu M. Fluoroquinolone resistance in Helicobacter pylori: role of mutations at position 87 and 91 of GyrA on the level of resistance and identification of a resistance conferring mutation in GyrB. Helicobacter. 2012;17(1):36–42.PubMedCrossRef
144.
Ma K, Hutchins A, Sung SJ, Adams MW. Pyruvate ferredoxin oxidoreductase from the hyperthermophilic archaeon, Pyrococcus furiosus, functions as a CoA-dependent pyruvate decarboxylase. Proc Natl Acad Sci USA. 1997;94(18):9608–13.PubMedPubMedCentralCrossRef
145.
Li B, Steindel P, Haddad N, Elliott SJ. Maximizing (Electro)catalytic CO2 reduction with a ferredoxin-based reduction potential gradient. ACS Catal. 2021;11(7):4009–23.CrossRef
146.
Eram MS, Ma K. Decarboxylation of pyruvate to acetaldehyde for ethanol production by hyperthermophiles. Biomolecules. 2013;3(3):578–96.PubMedPubMedCentralCrossRef
147.
Gilbreath JJ, West AL, Pich OQ, Carpenter BM, Michel S, Merrell DS. Fur activates expression of the 2-oxoglutarate oxidoreductase genes (oorDABC) in Helicobacter pylori. J Bacteriol. 2012;194(23):6490–7.PubMedPubMedCentralCrossRef
148.
Su Z, Xu H, Zhang C, Shao S, Li L, Wang H, Wang H, Qiu G. Mutations in Helicobacter pylori porD and oorD genes may contribute to furazolidone resistance. Croat Med J. 2006;47(3):410–5.PubMedPubMedCentral
149.
Zamani M, Rahbar A, Shokri-Shirvani J. Resistance of Helicobacter pylori to furazolidone and levofloxacin: a viewpoint. World J Gastroenterol. 2017;23(37):6920–2.PubMedPubMedCentralCrossRef
150.
Kwon DH, El-Zaatari FA, Kato M, Osato MS, Reddy R, Yamaoka Y, Graham DY. Analysis of rdxA and involvement of additional genes encoding NAD(P)H flavin oxidoreductase (FrxA) and ferredoxin-like protein (FdxB) in metronidazole resistance of Helicobacter pylori. Antimicrob Agents Chemother. 2000;44(8):2133–42.PubMedPubMedCentralCrossRef
151.
Zhang S, Wang X, Wise MJ, He Y, Chen H, Liu A, Huang H, Young S, Tay CY, Marshall BJ, et al. Mutations of Helicobacter pylori RdxA are mainly related to the phylogenetic origin of the strain and not to metronidazole resistance. J Antimicrob Chemother. 2020;75(11):3152–5.PubMedCrossRef
152.
Gong Y, Zhai K, Sun L, He L, Wang H, Guo Y, Zhang J. RdxA diversity and mutations associated with metronidazole resistance of Helicobacter pylori. Microbiology spectrum. 2023;11(2): e0390322.PubMedCrossRef
153.
Jeong JY, Mukhopadhyay AK, Akada JK, Dailidiene D, Hoffman PS, Berg DE. Roles of FrxA and RdxA nitroreductases of Helicobacter pylori in susceptibility and resistance to metronidazole. J Bacteriol. 2001;183(17):5155–62.PubMedPubMedCentralCrossRef
154.
Azzaya D, Gantuya B, Oyuntsetseg K, Davaadorj D, Matsumoto T, Akada J, Yamaoka Y. High antibiotic resistance of Helicobacter pylori and its associated novel gene mutations among the mongolian population. Microorganisms. 2020;8(7):1062.PubMedPubMedCentralCrossRef
155.
Tanih NF, Ndip LM, Ndip RN. Characterisation of the genes encoding resistance to metronidazole (rdxA and frxA) and clarithromycin (the 23S-rRNA genes) in South African isolates of Helicobacter pylori. Ann Trop Med Parasitol. 2011;105(3):251–9.PubMedPubMedCentralCrossRef
156.
O’Brien RJ, Lyle MA, Snider DE Jr. Rifabutin (ansamycin LM 427): a new rifamycin-S derivative for the treatment of mycobacterial diseases. Rev Infect Dis. 1987;9(3):519–30.PubMedCrossRef
157.
Kunin CM. Antimicrobial activity of rifabutin. Clin Infect Dise. 1996;22(1):S3-13.CrossRef
158.
Heep M, Beck D, Bayerdörffer E, Lehn N. Rifampin and rifabutin resistance mechanism in Helicobacter pylori. Antimicrob Agents Chemother. 1999;43(6):1497–9.PubMedPubMedCentralCrossRef
159.
Wang G, Wilson TJ, Jiang Q, Taylor DE. Spontaneous mutations that confer antibiotic resistance in Helicobacter pylori. Antimicrob Agents Chemother. 2001;45(3):727–33.PubMedPubMedCentralCrossRef
160.
Glocker E, Bogdan C, Kist M. Characterization of rifampicin-resistant clinical Helicobacter pylori isolates from Germany. J Antimicrob Chemother. 2007;59(5):874–9.PubMedCrossRef
161.
Hu Y, Zhang M, Lu B, Dai J. Helicobacter pylori and antibiotic resistance, a continuing and intractable problem. Helicobacter. 2016;21(5):349–63.PubMedCrossRef
162.
Garibyan L, Huang T, Kim M, Wolff E, Nguyen A, Nguyen T, Diep A, Hu K, Iverson A, Yang H, et al. Use of the rpoB gene to determine the specificity of base substitution mutations on the Escherichia coli chromosome. DNA Repair. 2003;2(5):593–608.PubMedCrossRef
163.
Heep M, Rieger U, Beck D, Lehn N. Mutations in the beginning of the rpoB gene can induce resistance to rifamycins in both Helicobacter pylori and Mycobacterium tuberculosis. Antimicrob Agents Chemother. 2000;44(4):1075–7.PubMedPubMedCentralCrossRef
164.
Hays C, Burucoa C, Lehours P, Tran CT, Leleu A, Raymond J. Molecular characterization of Helicobacter pylori resistance to rifamycins. Helicobacter. 2018;23(1):e12451.CrossRef
165.
Elbehiry A, Marzouk E, Aldubaib M, Abalkhail A, Anagreyyah S, Anajirih N, Almuzaini AM, Rawway M, Alfadhel A, Draz A, et al. Helicobacter pylori infection: current status and future prospects on diagnostic, therapeutic and control challenges. Antibiotics. 2023;12(2):191.PubMedPubMedCentralCrossRef
166.
Cardoso VF, Francesko A, Ribeiro C, Bañobre-López M, Martins P, Lanceros-Mendez S. Advances in magnetic nanoparticles for biomedical applications. Adv Healthcare Mater. 2018;7(5):1700845.CrossRef
167.
Jenks PJ. Causes of failure of eradication of Helicobacter pylori. BMJ. 2002;325(7354):3–4.PubMedPubMedCentralCrossRef
168.
Salam MA, Al-Amin MY, Salam MT, Pawar JS, Akhter N, Rabaan AA, Alqumber MAA. Antimicrobial resistance: a growing serious threat for global public health. Healthcare. 2023;11(13):1946.PubMedPubMedCentralCrossRef
169.
Ng HY, Leung WK, Cheung KS. Antibiotic resistance, susceptibility testing and stewardship in Helicobacter pylori infection. Int J Mol Sci. 2023;24(14):11708.PubMedPubMedCentralCrossRef
170.
Bebell LM, Muiru AN. Antibiotic use and emerging resistance: how can resource-limited countries turn the tide? Glob Heart. 2014;9(3):347–58.PubMedCrossRef
171.
Park CH, Jung SY, Lee JW, Yang HJ, Kim JS, Kim BJ, Choi SI, Seo SI, Lee J, Kim JG. Developing operational definitions related to Helicobacter pylori eradication therapy. J Korean Med Sci. 2023;38(35): e278.PubMedPubMedCentralCrossRef
172.
O’Connor JP, Taneike I, O’Morain C. Improving compliance with Helicobacter pylori eradication therapy: when and how? Ther Adv Gastroenterol. 2009;2(5):273–9.CrossRef
173.
Rammohan R, Magam SG, Joy M, Natt D, Patel A, Tadikonda A, Desai J, Bunting S, Yost RM, Akande O, et al. Unpacking the racial gap: Helicobacter pylori infection clearance among different racial groups. Cureus. 2023;15(8): e43080.PubMedPubMedCentral
174.
Zali MR. Facing resistance of H.pylori infection. Gastroenterol Hepatol Bed Bench. 2011;4(1):3–11.PubMedPubMedCentral
175.
Galoș F, Boboc C, Ieșanu MI, Anghel M, Ioan A, Iana E, Coșoreanu MT, Boboc AA. Antibiotic resistance and therapeutic efficacy of Helicobacter pylori infection in pediatric patients-a tertiary center experience. Antibiotics. 2023;12(1):146.PubMedPubMedCentralCrossRef
176.
Mégraud F, Lehours P. Helicobacter pylori detection and antimicrobial susceptibility testing. Clin Microbiol Rev. 2007;20(2):280–322.PubMedPubMedCentralCrossRef
177.
Chen J, Huang Y, Ding Z, Liang X, Lu H. E-test or agar dilution for metronidazole susceptibility testing of Helicobacter pylori: importance of the prevalence of metronidazole resistance. Front Microbiol. 2022;13: 801537.PubMedPubMedCentralCrossRef
178.
Arslan N, Yılmaz Ö, Demiray-Gürbüz E. Importance of antimicrobial susceptibility testing for the management of eradication in Helicobacter pylori infection. World J Gastroenterol. 2017;23(16):2854–69.PubMedPubMedCentralCrossRef
179.
Thung I, Aramin H, Vavinskaya V, Gupta S, Park JY, Crowe SE, Valasek MA. Review article: the global emergence of Helicobacter pylori antibiotic resistance. Aliment Pharmacol Ther. 2016;43(4):514–33.PubMedCrossRef
180.
Phan TN, Tran VH, Tran TN, Le VA, Santona A, Rubino S, Paglietti B. Antimicrobial resistance in Helicobacter pylori: current situation and management strategy in Vietnam. J Infect Dev Ctries. 2015;9(6):609–13.PubMedCrossRef
181.
Miftahussurur M, Fauzia KA, Nusi IA, Setiawan PB, Syam AF, Waskito LA, Doohan D, Ratnasari N, Khomsan A, Adnyana IK, et al. E-test versus agar dilution for antibiotic susceptibility testing of Helicobacter pylori: a comparison study. BMC Res Notes. 2020;13(1):22.PubMedPubMedCentralCrossRef
182.
Pohl D, Keller PM, Bordier V, Wagner K. Review of current diagnostic methods and advances in Helicobacter pylori diagnostics in the era of next generation sequencing. World J Gastroenterol. 2019;25(32):4629–60.PubMedPubMedCentralCrossRef
183.
Kaprou GD, Bergšpica I, Alexa EA, Alvarez-Ordóñez A, Prieto M. Rapid methods for antimicrobial resistance diagnostics. Antibiotics. 2021;10(2):209.PubMedPubMedCentralCrossRef
184.
Ramírez-Lázaro MJ, Lario S, Quílez ME, Montserrat A, Bella MR, Junquera F, García-Martínez L, Casalots À, Parra T, Calvet X. Droplet digital PCR detects low-density infection in a significant proportion of Helicobacter pylori-negative gastric biopsies of dyspeptic patients. Clin Transl Gastroenterol. 2020;11(6): e00184.PubMedPubMedCentralCrossRef
185.
Lin HJ, Lo WC, Perng CL, Tseng GY, Li AF, Ou YH. Mucosal polymerase chain reaction for diagnosing Helicobacter pylori infection in patients with bleeding peptic ulcers. World J Gastroenterol. 2005;11(3):382–5.PubMedPubMedCentralCrossRef
186.
He Q, Wang JP, Osato M, Lachman LB. Real-time quantitative PCR for detection of Helicobacter pylori. J Clin Microbiol. 2002;40(10):3720–8.PubMedPubMedCentralCrossRef
187.
Weiss J, Tsang TK, Meng X, Zhang H, Kilner E, Wang E, Watkin W. Detection of Helicobacter pylori gastritis by PCR: correlation with inflammation scores and immunohistochemical and CLOtest findings. Am J Clin Pathol. 2008;129(1):89–96.PubMedCrossRef
188.
Chen T, Meng X, Zhang H, Tsang RW, Tsang TK. Comparing multiplex PCR and rapid urease test in the detection of H. pylori in patients on proton pump inhibitors. Gastroenterol Res Pract. 2012;2012:898276.PubMedPubMedCentralCrossRef
189.
Bik EM, Eckburg PB, Gill SR, Nelson KE, Purdom EA, Francois F, Perez-Perez G, Blaser MJ, Relman DA. Molecular analysis of the bacterial microbiota in the human stomach. Proc Natl Acad Sci USA. 2006;103(3):732–7.PubMedPubMedCentralCrossRef
190.
Thorell K, Bengtsson-Palme J, Liu OH, Palacios Gonzales RV, Nookaew I, Rabeneck L, Paszat L, Graham DY, Nielsen J, Lundin SB, et al. In vivo analysis of the viable microbiota and Helicobacter pylori transcriptome in gastric infection and early stages of carcinogenesis. Infect Immunit. 2017;85(10):10–128.CrossRef
191.
van Doorn LJ, Henskens Y, Nouhan N, Verschuuren A, Vreede R, Herbink P, Ponjee G, van Krimpen K, Blankenburg R, Scherpenisse J, et al. The efficacy of laboratory diagnosis of Helicobacter pylori infections in gastric biopsy specimens is related to bacterial density and vacA, cagA, and iceA genotypes. J Clin Microbiol. 2000;38(1):13–7.PubMedPubMedCentralCrossRef
192.
Quan PL, Sauzade M, Brouzes E. dPCR: a technology review. Sensors. 2018;18(4):1271.PubMedPubMedCentralCrossRef
193.
Hindson CM, Chevillet JR, Briggs HA, Gallichotte EN, Ruf IK, Hindson BJ, Vessella RL, Tewari M. Absolute quantification by droplet digital PCR versus analog real-time PCR. Nat Methods. 2013;10(10):1003–5.PubMedPubMedCentralCrossRef
194.
Cao L, Cui X, Hu J, Li Z, Choi JR, Yang Q, Lin M, Ying Hui L, Xu F. Advances in digital polymerase chain reaction (dPCR) and its emerging biomedical applications. Biosens Bioelectron. 2017;90:459–74.PubMedCrossRef
195.
Talarico S, Safaeian M, Gonzalez P, Hildesheim A, Herrero R, Porras C, Cortes B, Larson A, Fang FC, Salama NR. Quantitative detection and genotyping of Helicobacter pylori from stool using droplet digital PCR reveals variation in bacterial loads that correlates with cagA virulence gene carriage. Helicobacter. 2016;21(4):325–33.PubMedCrossRef
196.
Sun L, Talarico S, Yao L, He L, Self S, You Y, Zhang H, Zhang Y, Guo Y, Liu G, et al. Droplet digital PCR-based detection of clarithromycin resistance in Helicobacter pylori isolates reveals frequent Heteroresistance. J Clin Microbiol. 2018;56(9):10–128.CrossRef
197.
Talarico S, Korson AS, Leverich CK, Park S, Jalikis FG, Upton MP, Broussard E, Salama NR. High prevalence of Helicobacter pylori clarithromycin resistance mutations among Seattle patients measured by droplet digital PCR. Helicobacter. 2018;23(2): e12472.PubMedPubMedCentralCrossRef
198.
Ram MR, Teh X, Rajakumar T, Goh KL, Leow AHR, Poh BH, Mariappan V, Shankar EM, Loke MF, Vadivelu J. Polymorphisms in the host CYP2C19 gene and antibiotic-resistance attributes of Helicobacter pylori isolates influence the outcome of triple therapy. J Antimicrob Chemother. 2019;74(1):11–6.CrossRef
199.
Talarico S, Safaeian M, González P, Hildesheim A, Porras C, Cortes B, Larson A, Fang F, Salama N. Quantitative detection and genotyping of Helicobacter pylori from stool using droplet digital pcr reveals variation in bacterial loads that correlates with cagA virulence gene carriage. Helicobacter. 2015;21:325–33.PubMedPubMedCentralCrossRef
200.
Urgessa NA, Geethakumari P, Kampa P, Parchuri R, Bhandari R, Alnasser AR, Akram A, Kar S, Osman F, Mashat GD, et al. A comparison between histology and rapid urease test in the diagnosis of Helicobacter pylori in gastric biopsies: a systematic review. Cureus. 2023;15(5): e39360.PubMedPubMedCentral
201.
Kiga K, Tan XE, Ibarra-Chávez R, Watanabe S, Aiba Y, Sato’o Y, Li FY, Sasahara T, Cui B, Kawauchi M, et al. Development of CRISPR-Cas13a-based antimicrobials capable of sequence-specific killing of target bacteria. Nat Commun. 2020;11(1):2934.PubMedPubMedCentralCrossRef
202.
Mayorga-Ramos A, Zúñiga-Miranda J, Carrera-Pacheco SE, Barba-Ostria C, Guamán LP. CRISPR-cas-based antimicrobials: design, challenges, and bacterial mechanisms of resistance. ACS Infect Dis. 2023;9(7):1283–302.PubMedPubMedCentralCrossRef
203.
Wang Y, Liu L, Liu X, Wu K, Zhu X, Ma L, Su J. An ultrasensitive PCR-Based CRISPR-Cas13a method for the detection of Helicobacter pylori. J Personal Med. 2022;12(12):2082.CrossRef
204.
Zhang X, Qiu H, Zhong X, Yi S, Jia Z, Chen L, Hu S. A CRISPR/Cas12a-assisted array for Helicobacter pylori DNA analysis in saliva. Anal Chim Acta. 2023;1239: 340736.PubMedCrossRef
205.
Sukri A, Hanafiah A, Patil S, Lopes BS. The potential of alternative therapies and vaccine candidates against Helicobacter pylori. Pharmaceuticals. 2023;16(4):552.PubMedPubMedCentralCrossRef
206.
Bugaytsova JA, Piddubnyi A, Tkachenko I, Rakhimova L, Edlund JO, Thorell K, Marcotte H, Lundquist A, Schön K, Lycke N, et al. Vaccination with Helicobacter pylori attachment proteins protects against gastric cancer. BioRxiv. 2023. https://doi.org/10.1101/2023.05.25.542131.CrossRefPubMedPubMedCentral
207.
Sutton P, Boag JM. Status of vaccine research and development for Helicobacter pylori. Vaccine. 2019;37(50):7295–9.PubMedPubMedCentralCrossRef
208.
Haghighi FH, Menbari S, Mohammadzadeh R, Pishdadian A, Farsiani H. Developing a potent vaccine against Helicobacter pylori: critical considerations and challenges. Expert Rev Mol Med. 2024;27:1–61.
209.
Guo L, Zhang F, Wang S, Li R, Zhang L, Zhang Z, Yin R, Liu H, Liu K. Oral immunization with a M cell-targeting recombinant L. Lactis vaccine LL-plSAM-FVpE stimulate protective immunity against H. pylori in Mice. Front Immunol. 2022;13:918160.PubMedPubMedCentralCrossRef
210.
Kwong KW, Xin Y, Lai NC, Sung JC, Wu KC, Hamied YK, Sze ET, Lam DM. Oral vaccines: a better future of immunization. Vaccines. 2023;11(7):1232.PubMedPubMedCentralCrossRef
211.
Vela Ramirez JE, Sharpe LA, Peppas NA. Current state and challenges in developing oral vaccines. Adv Drug Deliv Rev. 2017;114:116–31.PubMedPubMedCentralCrossRef
212.
Carneiro FA, Cortines JdR, Essus VA, da Silva IBN: Chapter 4 - Vaccine engineering & structural vaccinology. In: System Vaccinology. Edited by Prajapati V: Academic Press; 2022: 55–86.
213.
Kim SH, Jung DI, Yang IY, Kim J, Lee KY, Nochi T, Kiyono H, Jang YS. M cells expressing the complement C5a receptor are efficient targets for mucosal vaccine delivery. Eur J Immunol. 2011;41(11):3219–29.PubMedCrossRef
214.
Ling J, Liao H, Clark R, Wong MS, Lo DD. Structural constraints for the binding of short peptides to claudin-4 revealed by surface plasmon resonance. J Biol Chem. 2008;283(45):30585–95.PubMedPubMedCentralCrossRef
215.
Yoo MK, Kang SK, Choi JH, Park IK, Na HS, Lee HC, Kim EB, Lee NK, Nah JW, Choi YJ, et al. Targeted delivery of chitosan nanoparticles to Peyer’s patch using M cell-homing peptide selected by phage display technique. Biomaterials. 2010;31(30):7738–47.PubMedCrossRef
216.
Helmy YA, Taha-Abdelaziz K, Hawwas HAE-H, Ghosh S, AlKafaas SS, Moawad MMM, Saied EM, Kassem II, Mawad AMM. Antimicrobial Resistance and Recent Alternatives to Antibiotics for the Control of Bacterial Pathogens with an Emphasis on Foodborne Pathogens. Antibiotics. 2023;12(2):274.PubMedPubMedCentralCrossRef
217.
Pereira EPV, van Tilburg MF, Florean E, Guedes MIF. Egg yolk antibodies (IgY) and their applications in human and veterinary health: a review. Int Immunopharmacol. 2019;73:293–303.PubMedPubMedCentralCrossRef
218.
Ulfman LH, Leusen JHW, Savelkoul HFJ, Warner JO, van Neerven RJJ. Effects of bovine immunoglobulins on immune function, allergy, and infection. Front Nutr. 2018;5:52.PubMedPubMedCentralCrossRef
219.
Müller S, Schubert A, Zajac J, Dyck T, Oelkrug C. IgY antibodies in human nutrition for disease prevention. Nutr J. 2015;14:109.PubMedPubMedCentralCrossRef
220.
Shin JH, Yang M, Nam SW, Kim JT, Myung NH, Bang WG, Roe IH. Use of egg yolk-derived immunoglobulin as an alternative to antibiotic treatment for control of Helicobacter pylori infection. Clin Diagn Lab Immunol. 2002;9(5):1061–6.PubMedPubMedCentral
221.
Suzuki H, Nomura S, Masaoka T, Goshima H, Kamata N, Kodama Y, Ishii H, Kitajima M, Nomoto K, Hibi T. Effect of dietary anti-Helicobacter pylori-urease immunoglobulin Y on Helicobacter pylori infection. Aliment Pharmacol Ther. 2004;20(Suppl 1):185–92.PubMedCrossRef
222.
Guo R, Wu S, Guan L, Xie Y, Yang X, Li Z, Zhang Z. Dietary multivalent anti-Helicobacter pylori immunoglobulin Y significantly increase the H. pylori eradication and improve the clinical symptoms in patients. Helicobacter. 2021;26(5):e12843.PubMedCrossRef
223.
Borhani K, Mobarez AM, Khabiri AR, Behmanesh M, Khoramabadi N. Production of specific IgY Helicobacter pylori recombinant OipA protein and assessment of its inhibitory effects towards attachment of H. pylori to AGS cell line. Clin Exp Vacc Res. 2015;4(2):177–83.CrossRef
224.
El-Kafrawy SA, Abbas AT, Oelkrug C, Tahoon M, Ezzat S, Zumla A, Azhar EI. IgY antibodies: the promising potential to overcome antibiotic resistance. Front Immunol. 2023;14:1065353.PubMedPubMedCentralCrossRef
225.
den Hoed CM, de Vries AC, Mensink PB, Dierikx CM, Suzuki H, Capelle L, van Dekken H, Ouwendijk R, Kuipers EJ. Bovine antibody-based oral immunotherapy for reduction of intragastric Helicobacter pylori colonization: a randomized clinical trial. Canadian J Gastroenterol. 2011;25(4):207–13.CrossRef
226.
Thomas JE, Austin S, Dale A, McClean P, Harding M, Coward WA, Weaver LT. Protection by human milk IgA against Helicobacter pylori infection in infancy. Lancet. 1993;342(8863):121.PubMedCrossRef
227.
Casswall TH, Sarker SA, Albert MJ, Fuchs GJ, Bergström M, Björck L, Hammarström L. Treatment of Helicobacter pylori infection in infants in rural Bangladesh with oral immunoglobulins from hyperimmune bovine colostrum. Aliment Pharmacol Ther. 1998;12(6):563–8.PubMedCrossRef
228.
Casswall TH, Nilsson HO, Björck L, Sjöstedt S, Xu L, Nord CK, Borén T, Wadström T, Hammarström L. Bovine anti-Helicobacter pylori antibodies for oral immunotherapy. Scand J Gastroenterol. 2002;37(12):1380–5.PubMedCrossRef
229.
Peypar MH, Yeganeh AV, Ramazani A, Alizadeh A, Abdorrashidi M, Tohidinia A, Shamlou MM, Heiat M. Oral immunotherapy for Helicobacter pylori: can it be trusted? A systematic review. Helicobacter. 2024;29(2): e13067.PubMedCrossRef
230.
Yin X, Lai Y, Du Y, Zhang T, Gao J, Li Z. Metal-based nanoparticles: a prospective strategy for Helicobacter pylori treatment. Int J Nanomed. 2023;18:2413–29.CrossRef
231.
Sannathimmappa MB, Nambiar V, Aravindakshan R. Antibiotics at the crossroads–do we have any therapeutic alternatives to control the emergence and spread of antimicrobial resistance? J Educat Health Promot. 2021;10:438.CrossRef
232.
Wang L, Hu C, Shao L. The antimicrobial activity of nanoparticles: present situation and prospects for the future. Int J Nanomed. 2017;12:1227–49.CrossRef
233.
Naganthran A, Verasoundarapandian G, Khalid FE, Masarudin MJ, Zulkharnain A, Nawawi NM, Karim M, Che Abdullah CA, Ahmad SA. Synthesis, characterization and biomedical application of silver nanoparticles. Materials. 2022;15(2):427.PubMedPubMedCentralCrossRef
234.
Garg D, Sarkar A, Chand P, Bansal P, Gola D, Sharma S, Khantwal S, Surabhi H, Mehrotra R, Chauhan N, et al. Synthesis of silver nanoparticles utilizing various biological systems: mechanisms and applications-a review. Progress Biomater. 2020;9(3):81–95.CrossRef
Weniger Zuckerkonsum ist ein großer Hebel für die Prävention kardiovaskulärer Erkrankungen. Stattdessen auf Süßstoffe zu setzen, scheint aber nicht der richtige Weg zu sein.
Ein internationales Forschungsteam drängt, Menschen mit koronarer Herzkrankheit routinemäßig auf eine chronische Nierenerkrankung zu screenen, um so ein stark erhöhtes kardiovaskuläres Risiko rechtzeitig zu erkennen. Dafür soll nicht nur die eGFR, sondern auch der Albumin-Kreatinin-Quotient im Urin herangezogen werden.
Mithilfe sogenannter „digitaler Zwillinge“ konnten in einer kleinen Studie zur Ablationstherapie bei Patienten mit ventrikulären Tachykardien sehr gute Behandlungsergebnisse erzielt werden.
Zur medikamentösen Thromboseprophylaxe nach Gelenkersatz kann in bestimmten Fällen die Einnahme von Azetylsalizylsäure (ASS) als kostengünstige Alternative zu Heparinspritzen oder DOAK (direkten oralen Antikoagulanzien) erwogen werden. Dazu müssen allerdings bestimmte Voraussetzungen erfüllt sein.
