Abstract
Bismuth (Bi) combinations have been utilized for the treatment of bacterial infections. In addition, these metal compounds are most frequently utilized for treating gastrointestinal diseases. Usually, Bi is found as bismuthinite (Bi sulfide), bismite (Bi oxide), and bismuthite (Bi carbonate). Newly, Bi nanoparticles (BiNP) were produced for CT imaging or photothermal treatment and nanocarriers for medicine transfer. Further benefits, such as increased biocompatibility and specific surface area, are also seen in regular-size BiNPs. Low toxicity and ecologically favorable attributes have generated interest in BiNPs for biomedical approaches. Moreover, BiNPs offer an option for treating multidrug-resistant (MDR) bacteria because they communicate directly with the bacterial cell wall, induce adaptive and inherent immune reactions, generate reactive oxygen compounds, limit biofilm production, and stimulate intracellular impacts. In addition, BiNPs in amalgamation with X-ray therapy as well as have the capability to treat MDR bacteria. BiNPs as photothermal agents can realize the actual antibacterial through continuous efforts of investigators in the near future. In this article, we summarized the properties of BiNPs, and different preparation methods, also reviewed the latest advances in the BiNPs’ performance and their therapeutic effects on various bacterial infections, such as Helicobacter pylori, Staphylococcus aureus, Pseudomonas aeruginosa, and Escherichia coli.
Graphical abstract: BiNPs are antibacterial and ideal photothermal agents to inhibit various bacterial infections
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Introduction
The constituents of nanoparticles (NPs) allow for a simple categorization into organic and inorganic categories (Oveili et al. 2023; Yasamineh et al. 2023). Antigen conveyance as vaccination is ideal for inorganic NPs because of their tiny size, improved constancy, controlled adjustability, higher penetrance, superior drug loadings, and triggered release profile. These cutting-edge developments, known as hybrid inorganic NPs, often have an inorganic core surrounded by an organic shell (Gholizadeh et al. 2022; Yasamineh et al. 2022a, b). Among these methods, NPs, which generally range in size from 0.2 to 100 nm, performed well as new antimicrobial substances (Panáček et al. 2006). Nanotechnology, regarded as an interdisciplinary technology, has several applications; some of them include pharmacology, medical diagnostics, nutrition, chemistry, ecology, biotechnology, and even physical energy. Silver, magnesium, copper, titanium, zinc, gold, and bismuth (Bi) are the most common metals utilized for biomedical purposes (Dizaj et al. 2015; Rudramurthy et al. 2016). Metallic NPs, which may be manufactured in very minute sizes, have the capability of efficiently penetrating the peptidoglycan layer of bacterial cells (Siddiqi et al. 2018). Also, because of the anionic characteristics of lipopolysaccharides (LPS) and teichoic acids (TA), the negatively charged surfaces of bacterial cells have the potential to adsorb Cu2+, Ag+, and Zn2+ that are liberated by metallic NPs (Safarov et al. 2019). Bi compounds have been utilized in the cosmetics and pharmaceutical industries for more than 250 years (Udalova et al. 2008). Metal-containing medications have recently become prominent; one example is bismuth nanoparticles (BiNPs). Bi-based medicines have shown therapeutic efficacy in the treatment of wounds. The antibacterial properties of BiNPs have been verified in many lab tests (Neamati et al. 2023; Tiekink 2002). Bi is a metallic element of the 5 A group of the periodic table which are the pnictogens (atomic number (Z = 83)) with elements, including nitrogen (N), phosphorus (P), arsenic (As), and antimony (Sb). Further benefits, such as increased biocompatibility and specific surface area, are also seen in regular-size BiNPs. These characteristics make it an excellent medium for immobilizing proteins and enzymes (Mayorga-Martinez et al. 2013). The combinations of Bi attributes show an special improvement in exploiting singularly or concomitantly cytotoxicity and diagnostic efficacy (Bartoli et al., 2020). For example, the potential of influencing the release of donepezil hydrochloride (DO) through altering the current and voltage in the presence of bismuth ferrite (BiFeO3) results in an highly controllable and delicately tunable medicine release for Alzheimer’s disease treatment (Cesur et al. 2022). The bismuth tungstate (Bi2WO6) nanosheets have developed more opportunities for the rational preparation of novel electronic and biomedical nanosystems. The exceptional efficiency of Bi2WO6 makes it favorable as a multifunctional medicine delivery system for multimodal synergistic cancer treatment (Feng et al. 2018). In an investigation, the Bi2MoO6/HRP heterojunctions were prepared through hydrothermal treatment by Bi molybdate (Bi2MoO6) and hydrothermally treated red phosphorus (HRP). The remarkably effective and constant 5% Bi2MoO6/HRP composite was potentially successful in treating toxic heavy metals and pathogenic bacteria for water treatment (Tuerhong et al. 2022). In addition, Bi2MoO6/NH2-GO/PEG was offered as an effective and pH-sensitive anticancer drug delivery system (Sheykhisarem and Dehghani 2023). The production of additive-free bismuth vanadate (BiVO4) microspheres is used as an electrochemical sensor to determine the anti-tuberculosis medicine rifampicin (Li and Yan 2009). In addition, ultrafine photoetched BiVO4 nanorods improved with DSPE-PEG2000 (PEBVO@PEG NRs) were produced to attain in situ self-supply of oxygen (O2) and reactive oxygen species (ROS) for hypoxic cancer therapy (Yang et al. 2022).
Because of the limited toxicity, high atomic number, X-ray sensitivity, close-infrared driven semiconductor qualities, and low expense, highly efficient BiNPs with therapeutic activities show considerable potential for cancer diagnostics and treatments (Deng et al. 2018; Luo et al. 2013). BiNPs with a wide range of potential uses in the biomedical industry due to their low cost, low toxicity, and outstanding characteristics (Gomez et al. 2021). Dyspepsia, gastric ulcers, and Helicobacter Pylori infections are only a few examples of the many gastrointestinal diseases treated using Bi-based drugs. Its therapeutic use has recently been expanded to drug delivery, imaging, and biosensing, as well as possible therapies for cancer, multi-drug resistant (MDR) pathogens, and viral diseases (Griffith et al. 2021). It is assumed that BiNPs will not be hazardous to human cells since Bi subsalicylate is utilized to cure stomach disorders, and there have been no reports of any adverse consequences from exposure to BiNPs. No cytotoxic impact was seen when monkey kidney cells were exposed to BiNPs for 24 h at a final dosage of 2 mM (Claudio and Chellam 2014). Modern medical practice uses organic compounds of Bi (such as Bi subcitrate, Bi subsalicylate, and Bi subnitrate) as antibacterial agents (Chen et al. 2006; Mahony et al. 1999). Moreover, BiNPs offer an option for treating MDR bacteria because they communicate directly with the bacterial cell wall, induce adaptive and inherent immune reactions, generate reactive oxygen compounds, limit biofilm production, and stimulate intracellular impacts (AlMatar et al. 2018; Luo et al. 2013). The primary dangers related to communicable infections include the development of medication resistance, the scarcity and lack of variety in current therapies, and the advent of novel viruses, some of which can potentially cause global pandemics. Bi compounds have a long history of usage as antibacterial agents and recent research has shown that some Bi-based compounds and BiNPs display antibacterial action against bacterial diseases such as Staphylococcus aureus, H. pylori, Escherichia coli, and Pseudomonas aeruginosa (Hsu et al. 2018; Khameneh et al. 2016; Pop et al. 2022; Vazquez et al., 2020; Wu et al. 2023). In this article, we summarized the characteristics of BiNPs and the antibacterial properties of BiNPs, and their therapeutic effects on bacterial infections.
BiNPs properties and performance
As a heavy transition metal, Bi has a Pauling electronegativity of 2.02, a melting point of 271.5 °C, and a boiling temperature of 1564 °C. Poor thermal transmission (7.97 W/mK), rhombohedral structure density of 9.78 g/cm3, the electrical resistance of 1.29 µΩm at 20 °C, and thermal expansion of 13.4 μm/mK at 25 °C are some of its characteristics (Torrisi et al. 2018). Further to having a significant resistance to electricity for metal, the feature of Bi is that it expands when it freezes. It has a lower ability to conduct heat than any element except mercury (Briand and Burford 1999). Low toxicity and ecologically favorable attributes have generated interest in BiNPs for biomedical approaches. The low cost and abundance of Bi also make it an appealing material for various deployments. The semimetal bulk Bi has desirable properties for fabricating BiNPs of multiple shapes, sizes, and chemical compositions, including substantial magnetoresistance, large Fermi wavelengths, and robust diamagnetism. These Bi compounds, also known as Bi chalcogenides, are often found in the forms Bi2S3, Bi2O3, Bi2Se3, and Bi2Te3. Inherent electrical and optical characteristics of Bi chalcogenides nanostructures make them appropriate for various medical applications; nevertheless, these features are modified by their shape and crystal structure. The V-VI-VII ternary oxide semiconductor substances also include a subset of Bi compounds known as bi oxyhalides (BiOX, where X may be either Cl, Br, or I). These materials have gained considerable interest for photocatalytic performance under irradiation of visible light, in addition to electronics and energy storage, because of their layered formation and remarkable chemical resilience, as well as their electrical, optical, and mechanical characteristics. Moreover, Bi2WO6, BiFeO3, Bi2MoO6, BiPO4, BiVO4, Bi dimercaptopropanol (BisBAL), and (Bi2O)2CO3 nanostructures have been produced (Shahbazi et al. 2020). The majority of clinical experience using bi compounds has been in treating gastrointestinal diseases. Elemental Bi has antibacterial action, however, only at very high concentrations (on the millimolar scale) because of its poor solubility in water. Nevertheless, with chelation, solubility is improved, and Bi’s antibacterial characteristics are displayed at considerably lower concentrations (in the range of micromolar concentrations). For instance, BisBAL is particularly efficient against several different bacteria (Domenico et al. 1997; Velasco-Arias et al. 2012). Bismuth sulfide, Bismuth oxide, bismuth selenide, and bismuth telluride are just a few examples of non-metallic bismuth nanoparticles that have been synthesized and used for medicinal purposes. Bismuth is a very low-band-gap, diamagnetic semimetal. As a result of its unique combination of features, including strong magnetoresistance, thermal conductivity, and significant anisotropic electronic behavior, researchers have begun synthesizing BiNPs for electronic applications. BiNPs have also been investigated for their potential use as chemical catalysts. Newly developed BiNPs are effective in reducing 4-nitrophenol in the presence of NaBH4. Also, BiNPs’ photocatalytic action was described by Cui et al. (Cui et al. 2015; Gomez et al. 2021; Pothula et al. 2015; Thanh et al. 2014). Therefore, Bi2O3 NPs have potential medical, dental, and cosmetic applications because of their one-of-a-kind properties. These include, but are not limited to, their low cost and scalability, great stabilization, chemical inertness, nontoxicity, compatibility with living systems, and active properties (El-Batal et al. 2017) (Fig. 1).
Illustration of a high-Z bismuth nanoparticle (BiNP) (for example, a 50 nm BiNP consists of about 1 million Bi atoms). The targeting vector is selected to have a high degree of specificity for a biological receptor, including a cell surface protein (Winter et al. 2018)
Different methods to prepare BiNPs
Although several publications explain the synthesis and biological uses of non-metallic BiNPs, notably Bi chalcogenides and Bi oxyhalides such as Bi sulfide, Bi oxide, Bi selenide, and Bi telluride, only around fifty studies have reported the fabrication of metallic BiNPs. In medicine, Bi(III) complexes play an essential role. In the case of diarrhea and stomach distress brought on by overeating or drinking, Bi subsalicylate is often used. This one-time dosage medication comprises milligram amounts of Bi(III) in combination with salicylate. In order to treat infections caused by Helicobacter pylori, another Bi(III) complex called Bi subcitrate potassium is frequently utilized with antibiotics and blockers of proton pump activity (Gomez et al. 2021). Because of the spherical size-confined reverse micelles, the water-in-oil (w/o) microemulsion approach has been extensively used in the NPs synthesis process. The w/o microemulsion technique has produced several types of NPs, including Bi, TiO2, CdS, Pd, Rh, and Pt. Bi subcarbonate (BiO)2CO3 NPs were generated from Bi citrate by a w/o microemulsion-assisted hydrothermal technique to boost the antibacterial activity of Bi subcarbonate and perhaps discover novel Bi medicines (Chen et al. 2010; Cushing et al. 2004; Fang et al. 2001; Holmberg 2004). Moreover, 25 nm BiNPs were effectively generated using laser ablation, and these nanoparticles have the potential to serve as a better contrast medium for high-resolution imaging in a variety of biological contexts. BiNPs with robust anti-wear characteristics have been found to have an average size in the region of 50–103 nm when produced using conventional solvent procedures. The reduction of nitro chemicals into azo compounds is another use for BiNPs as catalysts. Colloidal-chemically made 40-nm BiNPs in an aqueous medium were shown to have significant antimicrobial action against various microbial pathogens (Das et al. 2020; Pothula et al. 2015; Rieznichenko, Gruzina et al., 2015; Torrisi et al. 2018).
Preliminary data on the thermoelectric characteristics of Bi nanopowders are presented, as is an efficient technique for preparing these nanoparticles by thermal breakdown of Bi dodecyl-mercaptide Bi(SC12H25)3. BiNPs are produced in the thermolysis process because the by-product dodecyl-disulfide acts as an effective capping agent, tightly bonding the surface of the Bi clusters to prohibit them from aggregating and slowing their development. Thermoelectric analysis of the synthesized Bi nanopowders shows unusual behavior, including a semimetal-semiconductor transition and, at the smallest grain size, a significantly elevated Seebeck coefficient compared with bulk Bi (170 nm) (Carotenuto et al. 2009).
The Bi Ferrite NPs (BiFeO3) used in cancer therapy are manufactured through the sol-gel technique from Bi nitrate (Bi (NO3)3.H2O) and iron nitrate (Fe (NO3)3.9H2O) as a foundation material. To prevent Bi volatilization and meet the need for nanosized oxides, the development of low-temperature fabrication techniques is crucial. Manufacturing BiFeO3 NPs using conventional solid-state methods results in low reproducibility, particle size increase, and the production of an impurity phase composed of Bi2O3 and Bi2Fe4O9 (Rameshkumar et al. 2021).
Pulsed laser ablation (PLA) of a Bi subsalicylate (BSS) target in an aqueous condition was identified as the most appropriate method for producing BSS NPs. Physical vapor deposition, or immersed PLA, is a method for creating NPs while preserving their original chemical and elemental makeup. A colloidal form of BSS was obtained since it has limited solubility in water (Castañeda et al., 2015; Yang 2012). For instance, metal nanoparticles were produced immediately by the pulsed laser ablation (Nd: YAG, = 1064 nm) of Bi and tellurium plates submerged in clean water. The findings showed that as the energy of the pulses increased, the NP concentration elevated while the average NP diameter reduced. The antibacterial capabilities of NPs are thought to be attributable to their overall surface area since a greater surface-to-volume ratio of TeNPs offers more efficient ways for improved antibacterial action against harmful microorganisms (Jassim et al. 2015) (Fig. 2).
Bi2O3 NPs were produced through the sol-gel technique. A combination of bismuth nitrate and citric acid solution is taken in an equal molar ratio (1:1) and heated in a hot water bath. In the evaporation of water, a gel is formed, which generates nanocrystalline Bi2O3 particles by decomposition at a temperature of 400 °C (Jha et al. 2005; Mallahi et al. 2014). Bi2O3 NPs are a proper option of metal oxide for several uses in the production of nanostructures, photocatalyst, catalytic performance for reduction, and photovoltaic, biological sciences, medical, biological, and antibacterial efficacy. These NPs are used in medical science, including an astringent in medical and topical cream (Abudayyak et al. 2017; Kazemi & Yaqoubi, 2020). The preparation of Bi2S3 NPs through the hot injection technique was investigated in addition to their behavior, when covered with a biocompatible factor. The hot injection technique allowed us to produce Bi2S3 nanorods measuring in mean 4.2 ± 1.4 nm in width and 27.5 ± 16.3 nm in length (Galain et al. 2022). In an investigation, researchers prepared and utilized Bi2S3 as a booster of X-ray radiation therapy. Moreover, Bi2S3 was used as a carrier of curcumin (CUR), an anti-cancer substance, for the aim of multimodality treatment (Nosrati et al. 2019). Bi chalcogenides-based nanomedicines have attracted much attention as exceptionally effective radiosensitizers because of their high photoelectric efficacy and excellent biocompatibility. In addition, particularly synthesized nanocomposites can successfully reduce the radiation resistance of cancer tissues (Huang et al. 2022). Bi chalcogenides (Bi13S18I2 and BiSI) were produced through the Solvothermal technique. The solvothermal preparation method has proven to be a very effective and affordable for generating BiNPs of designed composition. It has a higher capability to realize large-scale generation for many practical uses. This method needs utilizing a solvent at an average to high pressure ( generally between 1 atm and 10,000 atm) and temperature (usually between 100 and 1000 °C) to allow precursors to interact during preparation (Li et al. 2020; Song et al. 2015).
Laser ablation-made BiNPs. Polyol electrooxidation is facilitated by the generation of Bi(V) species. With the Bi(V) species, glucose undergoes more selective oxidation and C-C bond breakage, yielding arabinonic acid, erythronic acid, and ultimately glyceric acid instead of the more often observed gluconic acid as a result (Zheng et al. 2021)
The above-mentioned physical and chemical techniques require precision instruments, and the use of risky chemicals, and thus, green synthesis is ideal over other approaches. To produce metal NPs, bio-assisted methods, as well as recognized as biosynthesis or green synthesis, offer an eco-friendly, low-toxic, economical, and practical methodology that usages biological organizations, including bacteria, fungus, viruses, yeast, actinomycetes, plant extracts, and so on. Biosynthesized Bi2O3 NPs are inexpensive, more eco-friendly, easy to produce, and harmless to use than those made from microorganisms. Furthermore, compared to Bi2O3 NPs from microbes, biosynthesized Bi2O3 NPs are less dangerous since the solvents utilized to produce plant extracts are commonly distilled water and ethanol. Bi2O3 NPs from plant extracts are attained from different tree sections, such as the roots, barks, leaflets, flowers, fruit extracts, and peels (Prakash et al., 2022). In a study, BiNPs generating bacterial strain (designated as Delftia sp. SFG) was separated from salt marsh, and the biogenic BiNPs were purified, determined, and their cytotoxic and antioxidant actions were specified (Shakibaie et al. 2018). In another investigation, the Bi2O3 nanoflakes were prepared by a fruit peel extract of Nephelium lappaceum L.(Karnan and Samuel 2016). Presently, researchers utilize a one-step reduction manner to generate biomolecule-mediated BiNPs. BiNPs were prepared from various biomolecules, such as gelatin, bovine, and human serum albumin (Liu et al. 2020) (Table 1).
BiNPs inHelicobacter pylori.
To preserve the gastrointestinal mucosa and, more recently, to eliminate H. pylori, Bi-containing medications have been used on humans for almost 200 years (Himeno et al. 2022). One of the etiological causes of chronic gastritis, peptic ulcer disorder, and gastric cancer is H. pylori, the dominant member of the gastric microbiome of infected persons. Half of the world’s population may have H. pylori infection. H. pylori infection treatment is problematic due to the global rise in antibiotic resistance (Lee et al. 2022; Ren et al. 2022; Sousa et al. 2022). Nowadays, H. pylori is treated using Bi organic salts, which act as an antibacterial agent. For the first time, scientists have used a serial agar dilution technique to assess the antibacterial activity of elemental BiNPs against a variety of clinical isolates and a reference strain of H. pylori. All of the H. pylori strains put to the test were effectively countered by the antibacterial properties of these biogenic NPs. The obtained minimum inhibitory concentrations (MICs) for H. pylori (ATCC 26,695) and H. pylori clinical isolates ranged from 60 to 100 µg/ml. Formic acid, acetate, glutamate, glycine, valine, and uracil were among the metabolites secreted by H. pylori into their supernatants after exposure to an inhibitory dose of BiNPs (100 µg/ml). Inhibition of the nucleotide, Krebs cycle, and amino acid metabolism, as well as anti-H. pylori action, are all confirmed by these studies using NPs (Nazari et al. 2014). Another study found that the w/o microemulsion-assisted hydrothermal technique effectively synthesized well-crystallized Bi subcarbonate ((BiO)2CO3) NPs. Precursors employed in this synthesis are urea and Bi citrate, with the latter’s heat breakdown yielding the primary carbonate anion. Since the reactivity, nucleation, and growth processes are localized inside the water droplets, well-crystallized, monodisperse spherical NPs are produced. These NPs have anti-H. pylori effect comparable to those of the commercially utilized medication colloidal Bi subcitrate (CBS), suggesting that they may be helpful in building blocks for future nanomedicines (Chen et al. 2010). Due to the excellent efficacy of H. pylori eradication, Bi-comprising quadruple therapy (BQT), which contains proton pump inhibitor (PPI), Bi, and two antibiotics, is currently presented as first-line therapy. In an investigation, researchers showed that the patients eradicated through BQT had gut microbiota dysbiosis for more than one year. Moreover, the dysbiosis of the gut microbiome remarkably influenced human pathophysiology and was related to other diseases (Wu et al. 2022). Enhanced Bifidobacterium was detected in the gut microbiota after effective H. pylori eradication with 10-day BQT therapy (Guo et al. 2020). In another investigation, researchers demonstrated a remarkable decrease in the relative numbers of Bifidobacterium adolescentis, while Enterococcus faecium levels increased 0 or 2 days following the 14-day BQT therapy (Olekhnovich et al. 2019). Accordingly, it is essential to investigate the efficacy of H. pylori eradication treatment on the microbiota and the encouraging therapeutic methods to preserve gut microbiota homeostasis(Wu et al. 2022). In a study, researchers prepare a series of silica-covered Bi2S3 NPs (Bi2S3@SiO2) of several dimensions. 28 days following administration, Bi2S3@SiO2 NPs demonstrate low toxicity efficacy in vivo and nonsignificant effects on the construction and role of the gut microbiota in mice. This shows that no side effects on the gut homeostasis are stimulated through Bi2S3@SiO2 core-shell NPs and, therefore, they can act as very good and safe (Chen et al. 2022) (Table 2).
BiNPs in other bacterial infections
Oral plaque is the most prevalent biofilm, and Streptococcus mutans is the most frequent bacterium responsible for dental caries. In addition to being found in instances of endocarditis, S. mutans has been found colonizing the endocardium and heart valves. This is likely owing to S. mutans’ capacity to cling to solid surfaces and create a biofilm (Banas 2004; Lemos et al. 2019). Early research on the antibacterial properties of zerovalent BiNPs has shown promising results. They were equally effective as chlorhexidine in preventing the spread of S. mutans. When considering zero-valent BiNPs to add in a mouthwash, it is essential to remember that their MIC for bacterial growth suppression was 0.5 mM. Chlorhexidine, the gold standard in oral antiseptics, has been shown to have comparable efficacy to these NPs in the studies conducted. The production of biofilm by S. mutans was entirely halted by the use of zerovalent BiNPs. Zero-valent BiNPs were predicted to have a suppressive impact on cell development but not a total block; therefore, this finding was unexpected. Because NPs inactivated 69% of cells, researchers speculated that the remaining cells weren’t enough to create a biofilm. Most of the experimental data suggests that these NPs may be a viable option for combating biofilm-based bacterial infection (Hernandez et al., 2012). In less than 30 min, it was possible to use a chemical reduction technique to create BiNPs with a stable PVP coating. Scientists have developed a crystalline structure for tiny, stable, spherical BiNPs covered with PVP. In planktonic and biofilm growth conditions, the PVP-BiNPs demonstrated antifungal efficacy against the opportunistic pathogenic yeast Candida albicans and a significant antibacterial effect on the pathogenic bacterium Staphylococcus aureus (Vazquez et al., 2020a).
Bi dimercaptopropanol (BisBAL) has been demonstrated to significantly reduce biofilm development by inhibiting the ability of Staphylococcus aureus, Klebsiella pneumoniae, and Pseudomonas spp. to secrete extracellular polymeric substances (EPS) (Domenico et al. 1999, 2001). Brevundimonas diminuta EPS expression was dramatically suppressed in suspension cultures at concentrations slightly below the MIC when Bi was combined with a lipophilic dithiol (3-dimercapto-1-propanol, BAL) at a molar ratio of 2:1. A slime-like EPS matrix generated by B. diminuta led to biofouling and poor hydrodynamic backwashing of microfiltration membranes in the absence of BisBAL treatment (Badireddy et al. 2008). BisBAL NPs were produced in another work by reducing sodium borohydride in water at ambient temperature. This research examined how BisBAL NPs influence Pseudomonas aeruginosa’s capacity for growth, adhesion, and biofilm formation. NP characterization revealed they were highly lipophilic, with a rhombohedral crystalline form and a crystallite size of about 18 nm. If administered at or above the MIC = 12.5 micromolar, bacterial growth is entirely stifled for at least 30 days. In the study, researchers demonstrate that lipophilic BisBAL NPs at the MIC prevented bacterial adhesion to track-etched polycarbonate membrane surfaces and lysed bacteria entrenched in biofilms within 1 h of contact (Badireddy et al. 2013).
Compared to other Bi salts, the antibacterial activity of Bi thiols is up to a thousand times higher, making them effective antibiofilm agents. According to the results of susceptibility tests, including agar diffusion and broth dilution, staphylococci are highly vulnerable. At concentrations ranging from 0.9 to 1.8 µM Bi3+, bi-ethanedithiol inhibited 10 strains of methicillin-resistant Staphylococcus epidermidis, Staphylococcus aureus ATCC 25,923 at 2.4 µM Bi3+, and S. epidermidis ATCC 12,228 at 0.1 µM Bi3+. S. aureus resistant to antiseptics, was susceptible to BisBAL at a concentration of ≤ 7 µM Bi3+. S. epidermidis was inhibited for 39 days by hydrogel-coated polyurethane rods that had been soaked in BisBAL (suppressive area diameter in agar, ≥ 30 mm for more than 25 days). At subinhibitory doses, the production of slime by 16 slime-producing S. epidermidis strains was strongly suppressed by Bi-3,4-dimercaptotoluene (BisTOL), whereas it was unaffected by AgNO3. To sum up, bi-thiols are not only bactericidal and bacteriostatic against staphylococci, even species that are resistant to them, but they are also inhibitors of slime at doses below those required for complete inhibition. BisTOL may be beneficial in avoiding the infection and colonization of indwelling intravascular lines if administered at doses below those required to suppress growth, given that staphylococci are significant pathogens in this environment (Domenico et al. 2001).
The most prevalent species responsible for tooth caries and biofilm production are Streptococcus salivarius and Enterococcus faecalis. The most effective method for eradicating these germs is a 7-day course of chlorhexidine 2% mouthwash. For Streptococcus salivarius and Enterococcus faecalis, the MICs of BiNP suspension were 2.5 and 5 µg/ml, respectively. BiNP suspension has a minimum bactericidal concentration (MBC) of 5 µg/ml against Streptococcus salivarius and 10 µg/ml against Enterococcus faecalis. BiNPs were compared to a 2% chlorhexidine solution for their antibacterial efficacy. When tested against Streptococcus salivarius and Enterococcus faecalis, MICs of BiNPs were 5% less than those of chlorhexidine. MBC of BiNPs was 10% less than that of chlorhexidine against both bacteria. It was shown that BiNPs outperformed chlorhexidine and had lower MICs and MBCs (Rostamifar et al. 2021). The co-precipitation approach was used to successfully create Bi oxychloride (BiOCl) NPs at ambient temperature. BiOCl NPs showed considerable suppressive action at both MIC and MBC levels against the infectious bacterial strains S.aureus and P.aeruginosa. Importantly, BiOCl NPs are non-toxic to human erythrocytes, and they inhibit the activity of the coagulation system in both platelet-rich plasma (PRP) and platelet-poor plasma (PPP) (Puttaraju et al. 2022). P. aeruginosa’s capacity for quorum sensing and generation of biofilm was the subject of another research, which assessed the impact that tobramycin loaded on niosomes and combined with Bi-ethanedithiol had on these processes. Niosomal tobramycin and niosomal tobramycin combined with Bi-ethanedithiol dramatically lowered the MIC of tobramycin, and together they were the most effective combination for preventing the development of several P. aeruginosa strains. Biofilm development was significantly decreased by these chemicals at sub-MIC concentrations, and AHL molecule synthesis was substantially suppressed compared to untreated bacteria. MIC of Tobramycin was decreased, and biofilm development was efficiently suppressed by encapsulation in niosomes along with Bi-ethanedithiol (Mahdiun et al. 2017).
Bi subsalicylate (BSS) NPs were tested for their antibacterial efficacy against four common opportunistic pathogens: Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus, and Staphylococcus epidermidis. The production of BSS NPs was accomplished by performing pulse laser ablation on a solid target while it was suspended in distilled water and subjected to a variety of circumstances. Inhibition ratios for E. coli and S. epidermidis were found to be dose and size-dependent, whereas P. aeruginosa and S. aureus were shown to be more susceptible to the BSS NPs regardless of size or concentration. To achieve inhibition ratios > 80%, comparable to or greater than those achieved with the antibiotic employed as control, the BSS colloids with an average particle dimension of 20 nm were often the most effective. These findings prove that BSS colloids have promising medicinal uses as potent antibacterial agents (Castañeda et al., 2015). It was hypothesized that adding BisBAL NPs to mineral trioxide aggregate (MTA) would improve its already impressive antibacterial and antibiofilm capabilities; therefore, that was the focus of the study. After just 24 h of treatment, the biofilm of fluorescent E. faecalis was detached, and the growth of Enterococcus faecalis, Escherichia coli, and Candida albicans was suppressed by MTA-BisBAL NPs. The physical characteristics of MTA were not substantially altered by adding BisBAL NPs, and MTA-BisBAL NPs did not cause cytotoxicity in human gingival fibroblasts. Overall, these data imply that BisBAL NPs give antibacterial and antibiofilm capabilities to MTA while maintaining their biophysical features and without causing any adverse impacts on human gingival fibroblasts (Delgadillo et al., 2017).
Another study compared the MICs of three different colloidal dispersions of BiNPs to those of silver NPs to combat oral and nosocomial bacteria. Chemical reduction in DMSO was used to produce the NPs. Eight typical species of the subgingival biofilm and three species of medical interest (Pseudomonas aeruginosa, Staphylococcus aureus, and Escherichia coli) were examined to determine MICs for each colloidal dispersion. All of the Bi compounds exhibited antibacterial activity against the tested bacterial species, with MICs ranging from 37 to 329 µg/mL. Nevertheless, AgNPs revealed MICs between 16 and 32 µg/mL against bacteria in subgingival biofilm and between 32 and 65 µg/mL against medically essential species. The Bi2O3 NPs became the most effectual nanometric Bi compounds that were examined for this study, although having a lesser strength than AgNps (Campos et al. 2018).
BiNPs as photothermal agents in bacterial infection
Heavy element NPs (including gold and Bi) may be employed as radiosensitizers to increase the radiation dosage for bacterial death because of their broad cross-section for X-ray absorbance and photoelectron production (Kong et al. 2008; Wang et al. 2010; Werner et al. 2011). Nano-structured Bi has been the subject of theoretical investigation, with promising results suggesting it might be used in optical and electrooptic device applications, as well as having improved thermoelectric properties and functioning as a catalyst (Ma et al. 2013). Moreover, a technique based on enhancing X-ray irradiation by NPs can be employed to eradicate MDR microorganisms. In a proof-of-concept study, MDR P. aeruginosa was used as an example. In this experiment, polyclonal antibody-altered BiNPs were put into the microbial culture to target P. aeruginosa selectively. When MDR P. aeruginosa was exposed to X-rays at 40 kVp along with 200 ϻg ml− 1 BiNPs for 10 min, the results showed that up to 90% of the bacteria were killed. However, when BiNPs were not present, only around 6% of the bacteria were destroyed. A 35-fold increase in localized X-ray dosage is seen when 200 ϻg ml− 1 BiNPs are used, compared to a control without NPs. In addition, no significant detrimental impacts on human cells (MG-63 and HeLa cells) were detected with 200 ϻg ml− 1 BiNPs and 10 min of 40 kVp X-ray irradiation exposures, which provides the potential for future clinical usage. This antibacterial approach can be employed efficiently in destroying deeply embedded MDR bacteria in vivo due to the high penetrability of X-rays to human tissue (Luo et al. 2013) (Fig. 3). Synergistic antibacterial treatment is being studied, and one study involves the creation of silver-BiNPs (Ag-Bi@SiO2 NPs) based on mesoporous silica. BiNP-generated hyperthermia may impair cell integrity and speed up Ag ion release, according to in vitro investigations; this phenomenon has been shown to have potent antibacterial effects against methicillin-resistant Staphylococcus aureus (MRSA). Also, when exposed to laser pulses, 100 µg mL− 1 Ag-Bi@SiO2 NPs can eradicate mature MRSA biofilms and reduce biomass by 69.5%, demonstrating a more potent therapeutic impact than either the Bi@SiO2 NPs along with laser irradiation (26.8%) or Ag-Bi@SiO2 NPs (without laser treatment, 30.8%) groups. In vivo data further, demonstrate that the Ag-Bi@SiO2 NPs bactericidal platform effectively eliminates about 95.4% of abscess germs and expedites abscess ablation. The photothermal enhancement of the antimicrobial property of Ag-Bi@SiO2 NPs suggests that they may be helpful as a nano-antibacterial medication for treating skin infections (Cao et al. 2020). There have always been significant obstacles to wound healing. Bacterial infections are a major cause of delayed recovery and even death. In one research, nanoparticles of Bi sulfide (Bi2S3 NPs) with a significant photothermal impact were integrated with hydrogels of sodium alginate and acrylamide (PAAm/NaAlg hydrogels) to create nanocomposite adhesive hydrogels (Bi2S3 NPs hydrogels) that exhibited potent antibacterial activity and were compatible with living organisms. Bi2S3 NPs are capable of efficiently converting light energy into heat energy and producing a specific quantity of reactive oxygen species (ROS) to break up bacterial proteins and damage cell membranes. Hydrogels have been shown to have an adhesion property and to stimulate wound healing without the use of growth factors in in vivo investigations. Hydrogels containing photothermal Bi2S3 NPs were first created for wound treatment; these hydrogels generated heat energy for bactericidal purposes when exposed to near-infrared (NIR) light (Zhou et al. 2023). A NIR light catalyst (Bi2S3–S-nitrosothiol–acetylcholine (BSNA)) was developed in another work by converting •O2– into peroxynitrite in situ; this compound may increase bacteria’s sensitivity to ROS and heat, killing them at a relatively low temperature. The in situ-transformed peroxynitrite has enhanced membrane-penetrating and antioxidant properties. BSNA NPs hindered bacterial glucose metabolism by reducing xerC/xerD expression, and by nitrifying TYR179, they altered the secondary structure of HSP70 and HSP90. The antibacterial activity was further enhanced by the synergistic action of the developed BSNA and clinical antibiotics. In the case of antibiotics belonging to the tetracycline family, BSNA NPs caused alterations in the structure of the phenolic hydroxyl group. They hindered the interaction between tetracycline and the targeted t-RNA recombinant protein. Moreover, BSNA’s immunotherapy action was shown by its ability to increase CD8 + T cell production and decrease the incidence of typical sequelae associated with peritonitis (Li et al. 2022).
Researchers in another work describe synthesizing unique palladium NPs coated Bi oxybromide (Pd/BiOBr) nanostructures utilizing an energy-efficient solution-based technique; these nanostructures exhibit potent photocatalytic antibacterial activity. It was determined how effective the photocatalytic antibacterial activity of Pd/BiOBr was against several Gram-positive and Gram-negative bacterial strains that are often considered to be pathogenic (Pseudomonas aeruginosa, Pseudomonas fluorescens, Aeromonas salmonicida, Escherichia coli, Klebsiella pneumoniae, Salmonella typhimurium, Bacillus subtilis). Pd/BiOBr demonstrated remarkable photocatalytic disinfection efficiency, with bacterial inhibition rates of more than 99.9%. Even at a low dose of 0.5 µg/mL, Pd/BiOBr substantially reduced the growth of bacteria in addition to 2 h of visible light irradiation; at 1 µg/mL, Pd/BiOBr totally killed all the evaluated bacterial strains, demonstrating their remarkable bactericidal power (Bisht et al. 2022) (Table 3).
BiNP improved the effectiveness of X-ray radiation in eliminating multidrug-resistant bacteria in deep tissue. The diagram illustrates the interaction between bacteria and BiNPs (Luo et al. 2013)
In vitro cytotoxicity of BiNPs
Various double-blind assessments have demonstrated that the blood Bi concentration of 50 µg/L (about 600 nM) is considered to be non-toxic during Bi compound injection, some adverse events, including Bi-stimulated encephalopathy, are still reported (Larsen et al. 2005). Meantime, 5.0 mg/L (about 10 µM) Bi2O3 can stimulate genotoxicity by enhancing the oxidative stress in the blood (Geyikoglu and Turkez 2005). 200 mM Bi citrate exposed J774 cells accumulate the metal in their lysosomes and lead to lysosomal rupture (Stoltenberg et al. 2002). In vivo toxicity investigations as well as show that 100 µg/L colloidal Bi subnitrate can stimulate liver damage and cerebellar involvement. The BiNPs are non-toxic at a concentration of 0.5 nM. NPs at a great concentration (50 nM) kill 45, 52, 41, and 34% HeLa cells for bare nanoparticles, amine-terminated BiNPs, silica-covered BiNPs, and polyethylene glycol (PEG) modified BiNPs, respectively; which shows cytotoxicity in terms of cell viability is in the decreasing order of amine-terminated BiNPs, naked BiNPs, silica covered BiNPs, and PEG-modified BiNPs (Luo et al. 2012). The 200 µg/ml BiNPs improved localized X-ray dose by 35 times greater than the control with no NPs. Moreover, no remarkable adverse events on human cells (HeLa and MG-63 cells) have been detected with 200 µg/ml BiNPs and 10 min 40 kVp X-ray irradiation exposures (Luo et al. 2013). In a study, BiNPs synthesizing bacterial strain (determined as Delftia sp. SFG) was separated from salt marsh, and the biogenic BiNPs were purified, defined, and their cytotoxic and antioxidant functions were characterized. The achieved outcomes of cytotoxic effects (defined through the MTT-based colorimetric method) of the bare BiNPs revealed IC50 of 10.9 ± 0.9 µg/mL, 35.4 ± 0.5 µg/mL, and 42.8 ± 1.7 µg/mL versus A549, MCF-7, and 3T3 cell lines. The definition of antioxidant function demonstrated IC50 amounts of 123.1 µg/mL and 307.2 µg/mL for butylated hydroxyanisole (BHA) and BiNPs, respectively (Shakibaie et al. 2018).
BiNPs limitations and advantages in bacterial infection
Gold, Silver, zinc, and titanium metal NPs have all been studied extensively because of their purported antibacterial potential. Bi, on the other hand, is considered to be a “green” element because it does not cause cancer and has little bioaccumulation and cytotoxicity (Badireddy and Chellam 2014; Khan et al. 2016; Norman 1997; Norouzi et al. 2019; Yasamineh et al. 2023). Drugs containing Bi-based chemicals have found widespread application in the treatment of gastrointestinal diseases such as gastric ulcers, dyspepsia, and H. pylori infections. Nowadays, their medical applications have been expanded to include imaging, medication delivery, biosensing, and the treatment of viral infections, MRD microbial infections, cancer, and more (Griffith et al. 2021; Betancourt et al., 2022). Antimicrobial activities of BiNPs have been established in several lab experiments, and they have been successfully utilized to treat H. pylori ulcers in humans. For instance, one research (NCT04209933) intends to examine the effectiveness and safety of several types of Bi (pectin Bi nanoparticles, Bi potassium citrate, and pectin Bi capsules) in H. pylori first-line eradication. Patients with an H. pylori infection were randomized into 4 groups (1:1:1:1) and treated with a 14-day bismuth-containing quadruple therapy. The 4 groups received either bismuth potassium citrate capsules (220 mg), colloidal Bi pectin capsules (200 mg), bismuth pectin granules (150 mg), or bismuth pectin granules (300 mg). This research had a total of 240 individuals, although only 211 of those patients followed up for the whole trial duration. According to an intent-to-treat analysis, the 4 groups had H. pylori eradication levels of 73.3%, 76.7%, 75.0%, and 71.7%. The per-protocol assessment revealed that the 4 groups had respective removal rates of 86.3%, 82.1%, 83.3%, and 86.0% for H. pylori. The rate of H. pylori elimination did not vary significantly (P > .05) across the 4 study groups. There were no substantial differences among the 4 groups regarding the pace at which patients’ symptoms improved, the rate at which they had overall adverse reactions or the rate at which they complied with the treatment. To eliminate H. pylori, Bi pectin may be used instead of Bi potassium citrate in Bi-based quadruple treatment (Cao et al. 2021).
Also, because of Bi modest absorption (about 1% absorbed), it was assumed to be relatively non-toxic to humans. Generally speaking, Bi compounds are unstable and tend to precipitate in the stomach’s acidic environment, making Bi ion absorption in the gastrointestinal system challenging. Overdosing on colloidal Bi subcitrate (CBS) or other Bi compounds for extended periods has been proven in recent publications to cause reversible nephrotoxicity in both adults and children. Glucosuria, proteinuria, and elevated creatinine and plasma urea levels were all signs of renal impairment brought on by Bi. When shotgun pellets were implanted in the muscle, there was a greater chance for Bi to be maintained in the tubular cells of the kidney for a more extended period. In addition, decades ago, when Bi salts were taken orally, over twenty instances of acute encephalopathy were observed. To sum up, nephrotoxicity and neurotoxicity caused by Bi compounds have been established (Liu et al. 2017, 2018). Intoxication with Bi, including instances that ended in death, has been reported in human beings as a result of the use of Bi medications in the previous one hundred years. Acute renal dysfunction is triggered by a toxic dose of Bi compounds. Patients who had consumed overdoses of Bi over long periods experienced outbreaks of a reversible neurological disorder termed Bi encephalopathy in the 1970s. However, the dose-response association between Bi consumption and these symptoms is unknown, since many other persons who had taken substantial doses of Bi did not experience these symptoms (Himeno et al. 2022). Bi compounds have shown potential effectiveness in combating SARS-CoV-2 and associated diseases, as well as potent antimicrobial activity on a wide range of microorganisms. With the ability to accurately regulate the release of Bi ions for targeted medication delivery, Bi-containing materials can successfully attack pathogenic bacteria and cure the resulting infections and inflammatory disorders. Rapid and large-scale production of Bi-based particles is now a significant technological challenge (Huang et al. 2023). BiNPs constitute a favorable method for inhibiting various infectious diseases, but further evaluation is essential to ensure their safe utilization in humans. It is imperative to as well as look at the dosage of BiNPs. Therefore, further research on the possible cytotoxicity of BiNPs is essential to detect any adverse effects in humans (Liman 2013). There are fewer studies in this area. We can also investigate the impacts of various BiNPs on a wide range of bacteria. The functions of BiNPs can be highly improved when conjugated or covered with other materials. In fact, amalgamating NPs with antibiotics can help decrease microbial resistance. In resistant strains, alteration in the mode of function of antibiotics and the BiNPs improve the sensitivity of the microbe. The BiNPs can as well as act as a delivery system of antibiotics, thus simplifying access to bacterial cell walls. For example, Bi2O3 NPs are a promising material for medicine delivery methods and for improving the attributes of other products in medical uses (Mba and Nweze 2021; Szostak et al. 2019). The primary mechanism behind the function of BiNPs is still not well understood. The non-access to an accurate method for in vitro analysis, also the complication of the bacterial membrane, makes it hard to acquire appropriate insight into the precise mechanism for the antimicrobial function of BiNPs. To successfully assess the precise therapeutic potentials of BiNPs and unmask the microbial reaction to these factors, in vivo investigations are essential. In vivo investigations are indispensable to explain their use in biological systems thoroughly. Thus, more studies on the BiNPs activity at structural, genetic, and proteomic levels are essential (Gomez et al. 2021; Luo et al. 2012; Mba and Nweze 2021).
Conclusion
Infectious diseases are a leading cause of mortality across the globe and a threat to public health and the economy. They also have far-reaching, detrimental effects on various societal and economic facets. In the fight against infectious diseases, nanomaterials represent a promising novel tool. Although many nanotechnology-based medicines (nanopharmaceuticals) are now undergoing preclinical and clinical research, several nanotechnology-based pharmaceuticals are already accessible for use in healthcare, including vaccines and nano antibiotics. The in vitro antibacterial activity of BiNPs has been evaluated against a diverse range of high-pathogen microorganisms that may contribute to the development of diseases in humans and other animals. Moreover, BiNPs have been used to improve the efficiency of killing bacteria by photothermal means. As a result of their advantageous properties for imaging and medication administration, BiNPs hold much potential for the future of disease detection and treatment. The in vitro antibacterial activity of BiNPs against H. pylori was shown in a number of investigations, suggesting that these NPs may be effective in the future for chemotherapy of H. pylori. Healthcare facilities might benefit from the use of BiNPs as sanitizers and possible therapeutics for a variety of bacterial diseases. It would be prudent to do further studies on the antibacterial properties of BiNPs.
Data Availability
Not applicable.
Change history
11 August 2023
This article has been retracted. Please see the Retraction Notice for more detail: https://doi.org/10.1007/s11274-023-03724-y
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Salari Sedigh, S., Gholipour, A., zandi, M. et al. RETRACTED ARTICLE: The role of bismuth nanoparticles in the inhibition of bacterial infection. World J Microbiol Biotechnol 39, 190 (2023). https://doi.org/10.1007/s11274-023-03629-w
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DOI: https://doi.org/10.1007/s11274-023-03629-w