Abstract
Treatment of tuberculosis (TB) has been a therapeutic challenge because of not only the naturally high resistance level of Mycobacterium tuberculosis to antibiotics but also the newly acquired mutations that confer further resistance. Currently standardized regimens require patients to daily ingest up to four drugs under direct observation of a healthcare worker for a period of 6–9 months. Although they are quite effective in treating drug susceptible TB, these lengthy treatments often lead to patient non-adherence, which catalyzes for the emergence of M. tuberculosis strains that are increasingly resistant to the few available anti-TB drugs. The rapid evolution of M. tuberculosis, from mono-drug-resistant to multiple drug-resistant, extensively drug-resistant and most recently totally drug-resistant strains, is threatening to make TB once again an untreatable disease if new therapeutic options do not soon become available. Here, I discuss the molecular mechanisms by which M. tuberculosis confers its profound resistance to antibiotics. This knowledge may help in developing novel strategies for weakening drug resistance, thus enhancing the potency of available antibiotics against both drug susceptible and resistant M. tuberculosis strains.
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References
Adams KN, Takaki K, Connolly LE et al (2011) Drug tolerance in replicating mycobacteria mediated by a macrophage-induced efflux mechanism. Cell 145(1):39–53. doi:10.1016/j.cell.2011.02.022
Adilakshmi T, Ayling PD, Ratledge C (2000) Mutational analysis of a role for salicylic acid in iron metabolism of Mycobacterium smegmatis. J Bacteriol 182(2):264–271
Ainsa JA, Blokpoel MC, Otal I, Young DB, De Smet KA, Martin C (1998) Molecular cloning and characterization of Tap, a putative multidrug efflux pump present in Mycobacterium fortuitum and Mycobacterium tuberculosis. J Bacteriol 180(22):5836–5843
Alekshun MN, Levy SB (1997) Regulation of chromosomally mediated multiple antibiotic resistance: the mar regulon. Antimicrob Agents Chemother 41(10):2067–2075
Alexander DC, Ma JH, Guthrie JL, Blair J, Chedore P, Jamieson FB (2012) Gene sequencing for routine verification of pyrazinamide resistance in Mycobacterium tuberculosis: a role for pncA but not rpsA. J Clin Microbiol 50(11):3726–3728. doi:10.1128/JCM.00620-12
Andersson DI (2006) The biological cost of mutational antibiotic resistance: any practical conclusions? Curr Opin Microbiol 9(5):461–465. doi:10.1016/j.mib.2006.07.002
Andersson DI, Hughes D (2010) Antibiotic resistance and its cost: is it possible to reverse resistance? Nat Rev Microbiol 8(4):260–271. doi:10.1038/nrmicro2319
Andersson DI, Levin BR (1999) The biological cost of antibiotic resistance. Curr Opin Microbiol 2(5):489–493
Andini N, Nash KA (2006) Intrinsic macrolide resistance of the Mycobacterium tuberculosis complex is inducible. Antimicrob Agents Chemother 50(7):2560–2562. doi:10.1128/AAC.00264-06
Andriole VT (2005) The quinolones: past, present, and future. Clin Infect Dis 41(Suppl 2):S113–S119
Bamaga M, Wright DJ, Zhang H (2002) Selection of in vitro mutants of pyrazinamide-resistant Mycobacterium tuberculosis. Int J Antimicrob Agents 20(4):275–281
Bartek IL, Woolhiser LK, Baughn AD et al (2014) Mycobacterium tuberculosis Lsr2 is a global transcriptional regulator required for adaptation to changing oxygen levels and virulence. MBio 5(3):e01106–e01114. doi:10.1128/mBio.01106-14
Belisle JT, Vissa VD, Sievert T, Takayama K, Brennan PJ, Besra GS (1997) Role of the major antigen of Mycobacterium tuberculosis in cell wall biogenesis. Science 276(5317):1420–1422
Bernheim F (1940) The effect of salicylate on the oxygen uptake of the tubercle bacillus. Science 92(2383):204. doi:10.1126/science.92.2383.204
Betts JC, Lukey PT, Robb LC, McAdam RA, Duncan K (2002) Evaluation of a nutrient starvation model of Mycobacterium tuberculosis persistence by gene and protein expression profiling. Mol Microbiol 43(3):717–731
Birnbaum M, Koch R, Brendecke F (1891) Prof. Koch’s method to cure tuberculosis popularly treated. H.E. Haferkorn, Milwaukee
Boshoff HI, Mizrahi V (2000) Expression of Mycobacterium smegmatis pyrazinamidase in Mycobacterium tuberculosis confers hypersensitivity to pyrazinamide and related amides. J Bacteriol 182(19):5479–5485
Brennan PJ, Nikaido H (1995) The envelope of mycobacteria. Annu Rev Biochem 64:29–63
Buchmeier NA, Newton GL, Koledin T, Fahey RC (2003) Association of mycothiol with protection of Mycobacterium tuberculosis from toxic oxidants and antibiotics. Mol Microbiol 47(6):1723–1732
Burian J, Ramon-Garcia S, Sweet G, Gomez-Velasco A, Av-Gay Y, Thompson CJ (2012) The mycobacterial transcriptional regulator whiB7 gene links redox homeostasis and intrinsic antibiotic resistance. J Biol Chem 287(1):299–310. doi:10.1074/jbc.M111.302588
Burian J, Yim G, Hsing M et al (2013) The mycobacterial antibiotic resistance determinant WhiB7 acts as a transcriptional activator by binding the primary sigma factor SigA (RpoV). Nucleic Acids Res 41(22):10062–10076. doi:10.1093/nar/gkt751
Buriankova K, Doucet-Populaire F, Dorson O et al (2004) Molecular basis of intrinsic macrolide resistance in the Mycobacterium tuberculosis complex. Antimicrob Agents Chemother 48(1):143–150
Campbell PJ, Morlock GP, Sikes RD et al (2011) Molecular detection of mutations associated with first- and second-line drug resistance compared with conventional drug susceptibility testing of Mycobacterium tuberculosis. Antimicrob Agents Chemother 55(5):2032–2041. doi:10.1128/AAC.01550-10
Chakraborty S, Gruber T, Barry CE 3rd, Boshoff HI, Rhee KY (2013) Para-aminosalicylic acid acts as an alternative substrate of folate metabolism in Mycobacterium tuberculosis. Science 339(6115):88–91. doi:10.1126/science.1228980
Chambers HF, Moreau D, Yajko D et al (1995) Can penicillins and other β-lactam antibiotics be used to treat tuberculosis? Antimicrob Agents Chemother 39(12):2620–2624
Chao J, Wong D, Zheng X et al (2010) Protein kinase and phosphatase signaling in Mycobacterium tuberculosis physiology and pathogenesis. Biochim Biophys Acta 1804(3):620–627. doi:10.1016/j.bbapap.2009.09.008
Chen W, Biswas T, Porter VR, Tsodikov OV, Garneau-Tsodikova S (2011) Unusual regioversatility of acetyltransferase Eis, a cause of drug resistance in XDR-TB. Proc Natl Acad Sci USA 108(24):9804–9808. doi:10.1073/pnas.1105379108
Colangeli R, Helb D, Sridharan S et al (2005) The Mycobacterium tuberculosis iniA gene is essential for activity of an efflux pump that confers drug tolerance to both isoniazid and ethambutol. Mol Microbiol 55(6):1829–1840
Colangeli R, Helb D, Vilcheze C et al (2007) Transcriptional regulation of multi-drug tolerance and antibiotic-induced responses by the histone-like protein Lsr2 in M. tuberculosis. PLoS Pathog 3(6):e87
Colangeli R, Haq A, Arcus VL et al (2009) The multifunctional histone-like protein Lsr2 protects mycobacteria against reactive oxygen intermediates. Proc Natl Acad Sci USA 106(11):4414–4418. doi:10.1073/pnas.0810126106
Comas I, Borrell S, Roetzer A et al (2012) Whole-genome sequencing of rifampicin-resistant Mycobacterium tuberculosis strains identifies compensatory mutations in RNA polymerase genes. Nat Genet 44(1):106–110. doi:10.1038/ng.1038
Corbett EL, Watt CJ, Walker N et al (2003) The growing burden of tuberculosis: global trends and interactions with the HIV epidemic. Arch Intern Med 163(9):1009–1021. doi:10.1001/archinte.163.9.1009
D’Costa VM, McGrann KM, Hughes DW, Wright GD (2006) Sampling the antibiotic resistome. Science 311(5759):374–377. doi:10.1126/science.1120800
D’Costa VM, King CE, Kalan L et al (2011) Antibiotic resistance is ancient. Nature 477(7365):457–461. doi:10.1038/nature10388
da Silva PE, Von Groll A, Martin A, Palomino JC (2011) Efflux as a mechanism for drug resistance in Mycobacterium tuberculosis. FEMS Immunol Med Microbiol 63(1):1–9. doi:10.1111/j.1574-695X.2011.00831.x
Danilchanka O, Pavlenok M, Niederweis M (2008) Role of porins for uptake of antibiotics by Mycobacterium smegmatis. Antimicrob Agents Chemother 52(9):3127–3134. doi:10.1128/AAC.00239-08
Darzins E (1958) The bacteriology of tuberculosis. University of Minnesota Press, Minneapolis, pp 99–114
De Voss JJ, Rutter K, Schroeder BG, Su H, Zhu Y, Barry CE 3rd (2000) The salicylate-derived mycobactin siderophores of Mycobacterium tuberculosis are essential for growth in macrophages. Proc Natl Acad Sci USA 97(3):1252–1257
Demple B (2005) The nexus of oxidative stress responses and antibiotic resistance mechanisms in Escherichia coli and Salmonella. In: White DG, Alekshun MN, McDermott PF, Levy SB (eds) Frontiers in antimicrobial resistance: a tribute to Stuart B Levy. American Society for Microbiology, Washington, pp 191–197
Dhar N, McKinney JD (2010) Mycobacterium tuberculosis persistence mutants identified by screening in isoniazid-treated mice. Proc Natl Acad Sci USA 107(27):12275–12280. doi:10.1073/pnas.1003219107
Dorman SE, Chaisson RE (2007) From magic bullets back to the magic mountain: the rise of extensively drug-resistant tuberculosis. Nat Med 13(3):295–298. doi:10.1038/nm0307-295
Duncan K, Barry CE 3rd (2004) Prospects for new antitubercular drugs. Curr Opin Microbiol 7(5):460–465
Engstrom A, Perskvist N, Werngren J, Hoffner SE, Jureen P (2011) Comparison of clinical isolates and in vitro selected mutants reveals that tlyA is not a sensitive genetic marker for capreomycin resistance in Mycobacterium tuberculosis. J Antimicrob Chemother 66(6):1247–1254. doi:10.1093/jac/dkr109
Ferber D (2005) Biochemistry. Protein that mimics DNA helps tuberculosis bacteria resist antibiotics. Science 308(5727):1393
Flores AR, Parsons LM, Pavelka MS Jr (2005) Genetic analysis of the beta-lactamases of Mycobacterium tuberculosis and Mycobacterium smegmatis and susceptibility to β-lactam antibiotics. Microbiology 151(Pt 2):521–532
Gagneux S, Long CD, Small PM, Van T, Schoolnik GK, Bohannan BJ (2006) The competitive cost of antibiotic resistance in Mycobacterium tuberculosis. Science 312(5782):1944–1946. doi:10.1126/science.1124410
Gao LY, Laval F, Lawson EH et al (2003) Requirement for kasB in Mycobacterium mycolic acid biosynthesis, cell wall impermeability and intracellular survival: implications for therapy. Mol Microbiol 49(6):1547–1563
Garton NJ, Waddell SJ, Sherratt AL et al (2008) Cytological and transcript analyses reveal fat and lazy persister-like bacilli in tuberculous sputum. PLoS Med 5(4):e75. doi:10.1371/journal.pmed.0050075
Gengenbacher M, Kaufmann SH (2012) Mycobacterium tuberculosis: success through dormancy. FEMS Microbiol Rev 36(3):514–532. doi:10.1111/j.1574-6976.2012.00331.x
Gillespie SH, Billington OJ, Breathnach A, McHugh TD (2002) Multiple drug-resistant Mycobacterium tuberculosis: evidence for changing fitness following passage through human hosts. Microb Drug Resist 8(4):273–279. doi:10.1089/10766290260469534
Gomez JE, McKinney JD (2004) M. tuberculosis persistence, latency, and drug tolerance. Tuberculosis 84(1–2):29–44
Han JS, Lee JJ, Anandan T et al (2010) Characterization of a chromosomal toxin–antitoxin, Rv1102c–Rv1103c system in Mycobacterium tuberculosis. Biochem Biophys Res Commun 400(3):293–298. doi:10.1016/j.bbrc.2010.08.023
Hansen S, Lewis K, Vulic M (2008) Role of global regulators and nucleotide metabolism in antibiotic tolerance in Escherichia coli. Antimicrob Agents Chemother 52(8):2718–2726. doi:10.1128/AAC.00144-08
Hedgecock LW (1958) Mechanisms involved in the resistance of Mycobacterium tuberculosis to para-aminosalicylic acid. J Bacteriol 75(3):345–350
Hegde SS, Vetting MW, Roderick SL et al (2005) A fluoroquinolone resistance protein from Mycobacterium tuberculosis that mimics DNA. Science 308(5727):1480–1483
Hengge-Aronis R (2002) Signal transduction and regulatory mechanisms involved in control of the sigma(S) (RpoS) subunit of RNA polymerase. Microbiol Mol Biol Rev 66(3):373–395
Henry RJ (1943) The mode of action of sulfonamides. Bacteriol Rev 7(4):175–262
Hoffmann C, Leis A, Niederweis M, Plitzko JM, Engelhardt H (2008) Disclosure of the mycobacterial outer membrane: cryo-electron tomography and vitreous sections reveal the lipid bilayer structure. Proc Natl Acad Sci USA 105(10):3963–3967. doi:10.1073/pnas.0709530105
Houghton JL, Green KD, Pricer RE, Mayhoub AS, Garneau-Tsodikova S (2013) Unexpected N-acetylation of capreomycin by mycobacterial Eis enzymes. J Antimicrob Chemother 68(4):800–805. doi:10.1093/jac/dks497
Huang WL, Chi TL, Wu MH, Jou R (2011) Performance assessment of the GenoType MTBDRsl test and DNA sequencing for detection of second-line and ethambutol drug resistance among patients infected with multidrug-resistant Mycobacterium tuberculosis. J Clin Microbiol 49(7):2502–2508. doi:10.1128/JCM.00197-11
Hugonnet JE, Blanchard JS (2007) Irreversible inhibition of the Mycobacterium tuberculosis β-lactamase by clavulanate. Biochemistry 46(43):11998–12004. doi:10.1021/bi701506h
Ito K, Yamamoto K, Kawanishi S (1992) Manganese-mediated oxidative damage of cellular and isolated DNA by isoniazid and related hydrazines: non-Fenton-type hydroxyl radical formation. Biochemistry 31(46):11606–11613
Ivanovics G (1949) Antagonism between effects of p-aminosalicylic acid and salicylic acid on growth on M. tuberculosis. Proc Soc Exp Biol Med Soc Exp Biol Med 70(3):462
Jarlier V, Gutmann L, Nikaido H (1991) Interplay of cell wall barrier and β-lactamase activity determines high resistance to β-lactam antibiotics in Mycobacterium chelonae. Antimicrob Agents Chemother 35(9):1937–1939
Jindani A, Aber VR, Edwards EA, Mitchison DA (1980) The early bactericidal activity of drugs in patients with pulmonary tuberculosis. Am Rev Respir Dis 121(6):939–949. doi:10.1164/arrd.1980.121.6.939
Johansen SK, Maus CE, Plikaytis BB, Douthwaite S (2006) Capreomycin binds across the ribosomal subunit interface using tlyA-encoded 2′-O-methylations in 16S and 23S rRNAs. Mol Cell 23(2):173–182. doi:10.1016/j.molcel.2006.05.044
Kasik JE (1979) Mycobacterial β-Lactamases. In: Hamilton-Miller JMT, Smith JT (eds) β-Lactamases. Academic Press, London, p 500
Kasik JE, Peacham L (1968) Properties of β-lactamases produced by three species of mycobacteria. Biochem J 107(5):675–682
Keiler KC (2008) Biology of trans-translation. Annu Rev Microbiol 62:133–151. doi:10.1146/annurev.micro.62.081307.162948
Keren I, Shah D, Spoering A, Kaldalu N, Lewis K (2004) Specialized persister cells and the mechanism of multidrug tolerance in Escherichia coli. J Bacteriol 186(24):8172–8180. doi:10.1128/JB.186.24.8172-8180.2004
Keren I, Minami S, Rubin E, Lewis K (2011) Characterization and transcriptome analysis of Mycobacterium tuberculosis persisters. MBio 2(3):e00100–e00111. doi:10.1128/mBio.00100-11
Kim KH, An DR, Song J et al (2012) Mycobacterium tuberculosis Eis protein initiates suppression of host immune responses by acetylation of DUSP16/MKP-7. Proc Natl Acad Sci USA 109(20):7729–7734. doi:10.1073/pnas.1120251109
Kohanski MA, Dwyer DJ, Hayete B, Lawrence CA, Collins JJ (2007) A common mechanism of cellular death induced by bactericidal antibiotics. Cell 130(5):797–810. doi:10.1016/j.cell.2007.06.049
Kohanski MA, DePristo MA, Collins JJ (2010a) Sublethal antibiotic treatment leads to multidrug resistance via radical-induced mutagenesis. Mol Cell 37(3):311–320. doi:10.1016/j.molcel.2010.01.003
Kohanski MA, Dwyer DJ, Collins JJ (2010b) How antibiotics kill bacteria: from targets to networks. Nat Rev Microbiol 8(6):423–435. doi:10.1038/nrmicro2333
Lehmann J (1946) Para-aminosalicylic acid in the treatment of tuberculosis. Lancet 1(6384):15
Lewis K (2008) Multidrug tolerance of biofilms and persister cells. Curr Top Microbiol Immunol 322:107–131
Li Y, Zhang Y (2007) PhoU is a persistence switch involved in persister formation and tolerance to multiple antibiotics and stresses in Escherichia coli. Antimicrob Agents Chemother 51(6):2092–2099. doi:10.1128/AAC.00052-07
Liu J, Nikaido H (1999) A mutant of Mycobacterium smegmatis defective in the biosynthesis of mycolic acids accumulates meromycolates. Proc Natl Acad Sci USA 96(7):4011–4016
Liu J, Rosenberg EY, Nikaido H (1995) Fluidity of the lipid domain of cell wall from Mycobacterium chelonae. Proc Natl Acad Sci USA 92(24):11254–11258
Madsen CT, Jakobsen L, Buriankova K, Doucet-Populaire F, Pernodet JL, Douthwaite S (2005) Methyltransferase Erm(37) slips on rRNA to confer atypical resistance in Mycobacterium tuberculosis. J Biol Chem 280(47):38942–38947. doi:10.1074/jbc.M505727200
Mathys V, Wintjens R, Lefevre P et al (2009) Molecular genetics of para-aminosalicylic acid resistance in clinical isolates and spontaneous mutants of Mycobacterium tuberculosis. Antimicrob Agents Chemother 53(5):2100–2109. doi:10.1128/AAC.01197-08
Maus CE, Plikaytis BB, Shinnick TM (2005) Mutation of tlyA confers capreomycin resistance in Mycobacterium tuberculosis. Antimicrob Agents Chemother 49(2):571–577. doi:10.1128/AAC.49.2.571-577.2005
McCune RM Jr, Tompsett R (1956) Fate of Mycobacterium tuberculosis in mouse tissues as determined by the microbial enumeration technique. I. The persistence of drug-susceptible tubercle bacilli in the tissues despite prolonged antimicrobial therapy. J Exp Med 104(5):737–762
McCune RM Jr, McDermott W, Tompsett R (1956) The fate of Mycobacterium tuberculosis in mouse tissues as determined by the microbial enumeration technique. II. The conversion of tuberculous infection to the latent state by the administration of pyrazinamide and a companion drug. J Exp Med 104(5):763–802
McKenzie JL, Robson J, Berney M et al (2012) A VapBC toxin–antitoxin module is a posttranscriptional regulator of metabolic flux in mycobacteria. J Bacteriol 194(9):2189–2204. doi:10.1128/JB.06790-11
Michele TM, Ko C, Bishai WR (1999) Exposure to antibiotics induces expression of the Mycobacterium tuberculosis sigF gene: implications for chemotherapy against mycobacterial persistors. Antimicrob Agents Chemother 43(2):218–225
Montero C, Mateu G, Rodriguez R, Takiff H (2001) Intrinsic resistance of Mycobacterium smegmatis to fluoroquinolones may be influenced by new pentapeptide protein MfpA. Antimicrob Agents Chemother 45(12):3387–3392
Morais Cabral JH, Jackson AP, Smith CV, Shikotra N, Maxwell A, Liddington RC (1997) Crystal structure of the breakage-reunion domain of DNA gyrase. Nature 388(6645):903–906
Morris RP, Nguyen L, Gatfield J et al (2005) Ancestral antibiotic resistance in Mycobacterium tuberculosis. Proc Natl Acad Sci USA 102(34):12200–12205
Myers A (1963) Can tuberculosis be eradicated? Chest 43:327–329
Nagachar N, Ratledge C (2010) Knocking out salicylate biosynthesis genes in Mycobacterium smegmatis induces hypersensitivity to p-aminosalicylate (PAS). FEMS Microbiol Lett 311(2):193–199. doi:10.1111/j.1574-6968.2010.02091.x
Nampoothiri KM, Rubex R, Patel AK et al (2008) Molecular cloning, overexpression and biochemical characterization of hypothetical β-lactamases of Mycobacterium tuberculosis H37Rv. J Appl Microbiol 105(1):59–67. doi:10.1111/j.1365-2672.2007.03721.x
Nash KA (2003) Intrinsic macrolide resistance in Mycobacterium smegmatis is conferred by a novel erm gene, erm(38). Antimicrob Agents Chemother 47(10):3053–3060
Nash KA, Zhang Y, Brown-Elliott BA, Wallace RJ Jr (2005) Molecular basis of intrinsic macrolide resistance in clinical isolates of Mycobacterium fortuitum. J Antimicrob Chemother 55(2):170–177
Nguyen L (2012) Targeting antibiotic resistance mechanisms in Mycobacterium tuberculosis: recharging the old magic bullets. Expert Rev Anti Infect Ther. 10(9):963–965. doi:10.1586/eri.12.85
Nguyen L (2015) Microbes Cause Disease. In: Trefil J (ed) Discoveries in modern science: exploration, invention, technology, vol 2. Macmillan Reference USA, Farmington Hills, pp 695–699
Nguyen L, Jacobs MR (2012) Counterattacking drug-resistant tuberculosis: molecular strategies and future directions. Expert Rev Anti Infect Ther 10(9):959–961. doi:10.1586/eri.12.97
Nguyen L, Pieters J (2009) Mycobacterial subversion of chemotherapeutic reagents and host defense tactics: challenges in tuberculosis drug development. Annu Rev Pharmacol Toxicol 49:427–453. doi:10.1146/annurev-pharmtox-061008-103123
Nguyen L, Chinnapapagari S, Thompson CJ (2005) FbpA-Dependent biosynthesis of trehalose dimycolate is required for the intrinsic multidrug resistance, cell wall structure, and colonial morphology of Mycobacterium smegmatis. J Bacteriol 187(19):6603–6611
Niebisch A, Kabus A, Schultz C, Weil B, Bott M (2006) Corynebacterial protein kinase G controls 2-oxoglutarate dehydrogenase activity via the phosphorylation status of the OdhI protein. J Biol Chem 281(18):12300–12307. doi:10.1074/jbc.M512515200
Niederweis M (2003) Mycobacterial porins—new channel proteins in unique outer membranes. Mol Microbiol 49(5):1167–1177
Nikaido H (1994) Prevention of drug access to bacterial targets: permeability barriers and active efflux. Science 264(5157):382–388
Nishino K, Yamaguchi A (2001) Analysis of a complete library of putative drug transporter genes in Escherichia coli. J Bacteriol 183(20):5803–5812
Nopponpunth V, Sirawaraporn W, Greene PJ, Santi DV (1999) Cloning and expression of Mycobacterium tuberculosis and Mycobacterium leprae dihydropteroate synthase in Escherichia coli. J Bacteriol 181(21):6814–6821
Nott TJ, Kelly G, Stach L et al (2009) An intramolecular switch regulates phosphoindependent FHA domain interactions in Mycobacterium tuberculosis. Sci Signal 2(63):ra12. doi:10.1126/scisignal.2000212
O’Hare HM, Duran R, Cervenansky C et al (2008) Regulation of glutamate metabolism by protein kinases in mycobacteria. Mol Microbiol 70(6):1408–1423. doi:10.1111/j.1365-2958.2008.06489.x
Ormerod LP (2005) Multidrug-resistant tuberculosis (MDR-TB): epidemiology, prevention and treatment. Br Med Bull 73–74:17–24. doi:10.1093/bmb/ldh047
Philalay JS, Palermo CO, Hauge KA, Rustad TR, Cangelosi GA (2004) Genes required for intrinsic multidrug resistance in Mycobacterium avium. Antimicrob Agents Chemother 48(9):3412–3418
Quinting B, Reyrat JM, Monnaie D et al (1997) Contribution of β-lactamase production to the resistance of mycobacteria to β-lactam antibiotics. FEBS Lett 406(3):275–278
Ramon-Garcia S, Mick V, Dainese E et al (2012) Functional and genetic characterization of the tap efflux pump in Mycobacterium bovis BCG. Antimicrob Agents Chemother 56(4):2074–2083. doi:10.1128/AAC.05946-11
Ramon-Garcia S, Ng C, Jensen PR et al (2013) WhiB7, an Fe–S-dependent transcription factor that activates species-specific repertoires of drug resistance determinants in actinobacteria. J Biol Chem 288(48):34514–34528. doi:10.1074/jbc.M113.516385
Ratledge C (2004) Iron, mycobacteria and tuberculosis. Tuberculosis (Edinb) 84(1–2):110–130
Rawat M, Newton GL, Ko M, Martinez GJ, Fahey RC, Av-Gay Y (2002) Mycothiol-deficient Mycobacterium smegmatis mutants are hypersensitive to alkylating agents, free radicals, and antibiotics. Antimicrob Agents Chemother 46(11):3348–3355
Rengarajan J, Sassetti CM, Naroditskaya V, Sloutsky A, Bloom BR, Rubin EJ (2004) The folate pathway is a target for resistance to the drug para-aminosalicylic acid (PAS) in mycobacteria. Mol Microbiol 53(1):275–282. doi:10.1111/j.1365-2958.2004.04120.x
Reynolds MG (2000) Compensatory evolution in rifampin-resistant Escherichia coli. Genetics 156(4):1471–1481
Saguy M, Gillet R, Skorski P, Hermann-Le Denmat S, Felden B (2007) Ribosomal protein S1 influences trans-translation in vitro and in vivo. Nucleic Acids Res 35(7):2368–2376. doi:10.1093/nar/gkm100
Sala C, Haouz A, Saul FA et al (2009) Genome-wide regulon and crystal structure of BlaI (Rv1846c) from Mycobacterium tuberculosis. Mol Microbiol 71(5):1102–1116. doi:10.1111/j.1365-2958.2008.06583.x
Scanga CA, Mohan VP, Joseph H, Yu K, Chan J, Flynn JL (1999) Reactivation of latent tuberculosis: variations on the Cornell murine model. Infect Immun 67(9):4531–4538
Scorpio A, Zhang Y (1996) Mutations in pncA, a gene encoding pyrazinamidase/nicotinamidase, cause resistance to the antituberculous drug pyrazinamide in tubercle bacillus. Nat Med 2(6):662–667
Scorpio A, Lindholm-Levy P, Heifets L et al (1997) Characterization of pncA mutations in pyrazinamide-resistant Mycobacterium tuberculosis. Antimicrob Agents Chemother 41(3):540–543
Seidel H, Bittner J (1902) Darstellung der βm Aminosalicysäure. Monatsh Chem 23:431–433
Senaratne RH, Mobasheri H, Papavinasasundaram KG, Jenner P, Lea EJ, Draper P (1998) Expression of a gene for a porin-like protein of the OmpA family from Mycobacterium tuberculosis H37Rv. J Bacteriol 180(14):3541–3547
Sergeev R, Colijn C, Murray M, Cohen T (2012) Modeling the dynamic relationship between HIV and the risk of drug-resistant tuberculosis. Sci Transl Med 4(135):135ra67. doi:10.1126/scitranslmed.3003815
Sharp JD, Cruz JW, Raman S, Inouye M, Husson RN, Woychik NA (2012) Growth and translation inhibition through sequence-specific RNA binding by Mycobacterium tuberculosis VapC toxin. J Biol Chem 287(16):12835–12847. doi:10.1074/jbc.M112.340109
Sherman DR, Mdluli K, Hickey MJ et al (1996) Compensatory ahpC gene expression in isoniazid-resistant Mycobacterium tuberculosis. Science 272(5268):1641–1643
Shi W, Zhang Y (2010) PhoY2 but not PhoY1 is the PhoU homologue involved in persisters in Mycobacterium tuberculosis. J Antimicrob Chemother 65(6):1237–1242. doi:10.1093/jac/dkq103
Shi W, Zhang X, Jiang X et al (2011) Pyrazinamide inhibits trans-translation in Mycobacterium tuberculosis. Science 333(6049):1630–1632. doi:10.1126/science.1208813
Shiba T, Tsutsumi K, Yano H et al (1997) Inorganic polyphosphate and the induction of rpoS expression. Proc Natl Acad Sci USA 94(21):11210–11215
Singh A, Jain S, Gupta S, Das T, Tyagi AK (2003) mymA operon of Mycobacterium tuberculosis: its regulation and importance in the cell envelope. FEMS Microbiol Lett 227(1):53–63
Singh A, Gupta R, Vishwakarma RA et al (2005) Requirement of the mymA operon for appropriate cell wall ultrastructure and persistence of Mycobacterium tuberculosis in the spleens of guinea pigs. J Bacteriol 187(12):4173–4186
Siroy A, Mailaender C, Harder D et al (2008) Rv1698 of Mycobacterium tuberculosis represents a new class of channel-forming outer membrane proteins. J Biol Chem 283(26):17827–17837. doi:10.1074/jbc.M800866200
Stephan J, Mailaender C, Etienne G, Daffe M, Niederweis M (2004) Multidrug resistance of a porin deletion mutant of Mycobacterium smegmatis. Antimicrob Agents Chemother 48(11):4163–4170
Tan Y, Hu Z, Zhang T et al (2014) Role of pncA and rpsA gene sequencing in detection of pyrazinamide resistance in Mycobacterium tuberculosis isolates from southern China. J Clin Microbiol 52(1):291–297. doi:10.1128/JCM.01903-13
Thayil SM, Morrison N, Schechter N, Rubin H, Karakousis PC (2011) The role of the novel exopolyphosphatase MT0516 in Mycobacterium tuberculosis drug tolerance and persistence. PLoS One 6(11):e28076. doi:10.1371/journal.pone.0028076
Tian J, Bryk R, Itoh M, Suematsu M, Nathan C (2005) Variant tricarboxylic acid cycle in Mycobacterium tuberculosis: identification of α-ketoglutarate decarboxylase. Proc Natl Acad Sci USA 102(30):10670–10675. doi:10.1073/pnas.0501605102
Tremblay LW, Fan F, Blanchard JS (2010) Biochemical and structural characterization of Mycobacterium tuberculosis β-lactamase with the carbapenems ertapenem and doripenem. Biochemistry 49(17):3766–3773. doi:10.1021/bi100232q
Trnka L, Mison P (1988) Drugs and treatment regimens/p-aminosalicylic acid (PAS). In: Bartmann K (ed) Antituberculosis drugs. Handbook of experimental pharmacology. Springer, Berlin, pp 51–68
Udwadia ZF (2012) MDR, XDR, TDR tuberculosis: ominous progression. Thorax 67(4):286–288. doi:10.1136/thoraxjnl-2012-201663
Vilcheze C, Av-Gay Y, Attarian R et al (2008) Mycothiol biosynthesis is essential for ethionamide susceptibility in Mycobacterium tuberculosis. Mol Microbiol 69(5):1316–1329. doi:10.1111/j.1365-2958.2008.06365.x
Viveirosa M, Martins M, Rodrigues L et al (2012) Inhibitors of mycobacterial efflux pumps as potential boosters for anti-tubercular drugs. Expert Rev Anti Infect Ther 10(9):983–998. doi:10.1586/eri.12.89
Voladri RK, Lakey DL, Hennigan SH, Menzies BE, Edwards KM, Kernodle DS (1998) Recombinant expression and characterization of the major β-lactamase of Mycobacterium tuberculosis. Antimicrob Agents Chemother 42(6):1375–1381
Walburger A, Koul A, Ferrari G et al (2004) Protein kinase G from pathogenic mycobacteria promotes survival within macrophages. Science 304(5678):1800–1804
Wallis RS, Patil S, Cheon SH et al (1999) Drug tolerance in Mycobacterium tuberculosis. Antimicrob Agents Chemother 43(11):2600–2606
Wang JY, Burger RM, Drlica K (1998) Role of superoxide in catalase-peroxidase-mediated isoniazid action against mycobacteria. Antimicrob Agents Chemother 42(3):709–711
Wang F, Cassidy C, Sacchettini JC (2006) Crystal structure and activity studies of the Mycobacterium tuberculosis β-lactamase reveal its critical role in resistance to β-lactam antibiotics. Antimicrob Agents Chemother 50(8):2762–2771. doi:10.1128/AAC.00320-06
Wang X, Mitra N, Secundino I et al (2012) Specific inactivation of two immunomodulatory SIGLEC genes during human evolution. Proc Natl Acad Sci USA 109(25):9935–9940. doi:10.1073/pnas.1119459109
Watt B, Edwards JR, Rayner A, Grindey AJ, Harris G (1992) In vitro activity of meropenem and imipenem against mycobacteria: development of a daily antibiotic dosing schedule. Tuber Lung Dis 73(3):134–136. doi:10.1016/0962-8479(92)90145-A
Wayne LG, Hayes LG (1996) An in vitro model for sequential study of shiftdown of Mycobacterium tuberculosis through two stages of nonreplicating persistence. Infect Immun 64(6):2062–2069
Wei J, Dahl JL, Moulder JW et al (2000) Identification of a Mycobacterium tuberculosis gene that enhances mycobacterial survival in macrophages. J Bacteriol 182(2):377–384
Wissensehaftliche-ArbeRsgemeinsehaft-fur-die-Therapie-yon-Lungenkrankheiten (1969) Cooperative controlled trial of thiocarlide (DATC), PAS and bed rest alone in short-term single-drug treatment in retreated cavitary pulmonary tuberculosis. Beitrage zur Klinik und Erforschung der Tuberkulose und der Lungenkrankheiten 139(2):115–139
Wolff KA, Nguyen HT, Cartabuke RH, Singh A, Ogwang S, Nguyen L (2009) Protein kinase G is required for intrinsic antibiotic resistance in mycobacteria. Antimicrob Agents Chemother 53(8):3515–3519. doi:10.1128/AAC.00012-09
Wolff KA, de la Pena AH, Nguyen HT et al (2015) A redox regulatory system critical for mycobacterial survival in macrophages and biofilm development. PLoS Pathog 11(4):e1004839. doi:10.1371/journal.ppat.1004839
Wower IK, Zwieb CW, Guven SA, Wower J (2000) Binding and cross-linking of tmRNA to ribosomal protein S1, on and off the Escherichia coli ribosome. EMBO J 19(23):6612–6621. doi:10.1093/emboj/19.23.6612
Xie Z, Siddiqi N, Rubin EJ (2005) Differential antibiotic susceptibilities of starved Mycobacterium tuberculosis isolates. Antimicrob Agents Chemother 49(11):4778–4780. doi:10.1128/AAC.49.11.4778-4780.2005
Yang J, Liu Y, Bi J et al (2015) Structural basis for targeting the ribosomal protein S1 of Mycobacterium tuberculosis by pyrazinamide. Mol Microbiol 95(5):791–803. doi:10.1111/mmi.12892
Yaseen I, Kaur P, Nandicoori VK, Khosla S (2015) Mycobacteria modulate host epigenetic machinery by Rv1988 methylation of a non-tail arginine of histone H3. Nat Commun 6:8922. doi:10.1038/ncomms9922
Yegian D, Long RT (1951) The specific resistance of tubercle bacilli to para-aminosalicylic acid and sulfonamides. J Bacteriol 61(6):747–749
Youmans GP, Raleigh GW, Youmans AS (1947) The tuberculostatic action of para-aminosalicylic acid. J Bacteriol 54(4):409–416
Zaunbrecher MA, Sikes RD Jr, Metchock B, Shinnick TM, Posey JE (2009) Overexpression of the chromosomally encoded aminoglycoside acetyltransferase eis confers kanamycin resistance in Mycobacterium tuberculosis. Proc Natl Acad Sci USA 106(47):20004–20009. doi:10.1073/pnas.0907925106
Zhang Y, Heym B, Allen B, Young D, Cole S (1992) The catalase–peroxidase gene and isoniazid resistance of Mycobacterium tuberculosis. Nature 358(6387):591–593. doi:10.1038/358591a0
Zhang Y, Dhandayuthapani S, Deretic V (1996) Molecular basis for the exquisite sensitivity of Mycobacterium tuberculosis to isoniazid. Proc Natl Acad Sci USA 93(23):13212–13216
Zhang X, Liu L, Zhang Y, Dai G, Huang H, Jin Q (2015) Genetic determinants involved in p-aminosalicylic acid resistance in clinical isolates from tuberculosis patients in northern China from 2006 to 2012. Antimicrob Agents Chemother 59(2):1320–1324. doi:10.1128/AAC.03695-14
Zhao F, Wang XD, Erber LN et al (2014) Binding pocket alterations in dihydrofolate synthase confer resistance to para-aminosalicylic acid in clinical isolates of Mycobacterium tuberculosis. Antimicrob Agents Chemother 58(3):1479–1487. doi:10.1128/AAC.01775-13
Zheng J, Rubin EJ, Bifani P et al (2013) para-Aminosalicylic acid is a prodrug targeting dihydrofolate reductase in Mycobacterium tuberculosis. J Biol Chem 288(32):23447–23456. doi:10.1074/jbc.M113.475798
Zuber B, Chami M, Houssin C, Dubochet J, Griffiths G, Daffe M (2008) Direct visualization of the outer membrane of mycobacteria and corynebacteria in their native state. J Bacteriol 190(16):5672–5680. doi:10.1128/JB.01919-07
Acknowledgments
Work in the Nguyen laboratory is supported by NIH Grants R01AI087903 and R21AI119287.
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Nguyen, L. Antibiotic resistance mechanisms in M. tuberculosis: an update. Arch Toxicol 90, 1585–1604 (2016). https://doi.org/10.1007/s00204-016-1727-6
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DOI: https://doi.org/10.1007/s00204-016-1727-6