Skip to main content
SpringerLink
Log in

Molecular Biology of Drug Resistance in Mycobacterium tuberculosis

  • Chapter
  • First Online:
Pathogenesis of Mycobacterium tuberculosis and its Interaction with the Host Organism

Part of the book series: Current Topics in Microbiology and Immunology ((CT MICROBIOLOGY,volume 374))

Abstract

Tuberculosis (TB) has become a curable disease, thanks to the discovery of antibiotics. However, it has remained one of the most difficult infections to treat. Most current TB regimens consist of 6–9 months of daily doses of four drugs that are highly toxic to patients. The purpose of these lengthy treatments is to completely eradicate Mycobacterium tuberculosis, notorious for its ability to resist most antibacterial agents, thereby preventing the formation of drug resistant mutants. On the contrary, the prolonged therapies have led to poor patient adherence. This, together with a severe limit of drug choices, has resulted in the emergence of strains that are increasingly resistant to the few available antibiotics. Here, we review our current understanding of molecular mechanisms underlying the profound drug resistance of M. tuberculosis. This knowledge is essential for the development of more effective antibiotics, which are not only potent against drug resistant M. tuberculosis strains but also help shorten the current treatment courses required for drug susceptible TB.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  • Adams KN, Takaki K, Connolly LE et al (2011) Drug tolerance in replicating mycobacteria mediated by a macrophage-induced efflux mechanism. Cell 145:39–53

    PubMed  CAS  Google Scholar 

  • 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 180:5836–5843

    PubMed  CAS  Google Scholar 

  • Ainsa JA, Martin C, Gicquel B, Gomez-Lus R (1996) Characterization of the chromosomal aminoglycoside 2’-N-acetyltransferase gene from Mycobacterium fortuitum. Antimicrob Agents Chemother 40:2350–2355

    PubMed  CAS  Google Scholar 

  • Aldridge BB, Fernandez-Suarez M, Heller D, Ambravaneswaran V, Irimia D, Toner M, Fortune SM (2012) Asymmetry and aging of mycobacterial cells lead to variable growth and antibiotic susceptibility. Science 335:100–104

    PubMed  CAS  Google Scholar 

  • Alekshun MN, Levy SB (1997) Regulation of chromosomally mediated multiple antibiotic resistance: the mar regulon. Antimicrob Agents Chemother 41:2067–2075

    PubMed  CAS  Google Scholar 

  • Andersson DI (2006) The biological cost of mutational antibiotic resistance: any practical conclusions? Curr Opin Microbiol 9:461–465

    PubMed  CAS  Google Scholar 

  • Andersson DI, Hughes D (2010) Antibiotic resistance and its cost: is it possible to reverse resistance? Nature reviews. Microbiology 8:260–271

    PubMed  CAS  Google Scholar 

  • Andersson DI, Levin BR (1999) The biological cost of antibiotic resistance. Curr Opin Microbiol 2:489–493

    PubMed  CAS  Google Scholar 

  • Andini N, Nash KA (2006) Intrinsic macrolide resistance of the Mycobacterium tuberculosis complex is inducible. Antimicrob Agents Chemother 50:2560–2562

    PubMed  CAS  Google Scholar 

  • Andriole VT (2005) The quinolones: past, present, and future. Clin Infect Dis 41(Suppl 2):S113–S119

    PubMed  CAS  Google Scholar 

  • Bamaga M, Wright DJ, Zhang H (2002) Selection of in vitro mutants of pyrazinamide-resistant Mycobacterium tuberculosis. Int J Antimicrob Agents 20:275–281

    PubMed  CAS  Google Scholar 

  • 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 276:1420–1422

    PubMed  CAS  Google Scholar 

  • 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 43:717–731

    PubMed  CAS  Google Scholar 

  • Birnbaum M, Koch R, Brendecke F (1891) Prof. Koch’s method to cure tuberculosis popularly treated. H.E. Haferkorn, Milwaukee

    Google Scholar 

  • Boshoff HI, Mizrahi V (2000) Expression of Mycobacterium smegmatis pyrazinamidase in Mycobacterium tuberculosis confers hypersensitivity to pyrazinamide and related amides. J Bacteriol 182:5479–5485

    PubMed  CAS  Google Scholar 

  • Brennan PJ, Nikaido H (1995) The envelope of mycobacteria. Annu Rev Biochem 64:29–63

    PubMed  CAS  Google Scholar 

  • Buchmeier NA, Newton GL, Koledin T, Fahey RC (2003) Association of mycothiol with protection of Mycobacterium tuberculosis from toxic oxidants and antibiotics. Mol Microbiol 47:1723–1732

    PubMed  CAS  Google Scholar 

  • 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 287:299–310

    PubMed  CAS  Google Scholar 

  • Buriankova K, Doucet-Populaire F, Dorson O, Gondran A, Ghnassia JC, Weiser J, Pernodet JL (2004) Molecular basis of intrinsic macrolide resistance in the Mycobacterium tuberculosis complex. Antimicrob Agents Chemother 48:143–150

    PubMed  CAS  Google Scholar 

  • 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 55:2032–2041

    PubMed  CAS  Google Scholar 

  • Chambers HF, Moreau D, Yajko D et al (1995) Can penicillins and other beta-lactam antibiotics be used to treat tuberculosis? Antimicrob Agents Chemother 39:2620–2624

    PubMed  CAS  Google Scholar 

  • Chao J, Wong D, Zheng X, Poirier V, Bach H, Hmama Z, Av-Gay Y (2010) Protein kinase and phosphatase signaling in Mycobacterium tuberculosis physiology and pathogenesis. Biochim Biophys Acta 1804:620–627

    PubMed  CAS  Google Scholar 

  • 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 108:9804–9808

    PubMed  CAS  Google Scholar 

  • 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 106:4414–4418

    PubMed  CAS  Google Scholar 

  • 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 55:1829–1840

    PubMed  CAS  Google Scholar 

  • 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:e87

    PubMed  Google Scholar 

  • 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 44:106–110

    CAS  Google Scholar 

  • Corbett EL, Watt CJ, Walker N, Maher D, Williams BG, Raviglione MC, Dye C (2003) The growing burden of tuberculosis: global trends and interactions with the HIV epidemic. Arch Intern Med 163:1009–1021

    PubMed  Google Scholar 

  • D’Costa VM, King CE, Kalan L et al (2011) Antibiotic resistance is ancient. Nature 477:457–461

    PubMed  Google Scholar 

  • D’Costa VM, McGrann KM, Hughes DW, Wright GD (2006) Sampling the antibiotic resistome. Science 311:374–377

    PubMed  Google Scholar 

  • 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 63:1–9

    PubMed  Google Scholar 

  • Danilchanka O, Pavlenok M, Niederweis M (2008) Role of porins for uptake of antibiotics by Mycobacterium smegmatis. Antimicrobial Agents Chemother 52:3127–3134

    CAS  Google Scholar 

  • 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, DC, pp 191–197

    Google Scholar 

  • Dhar N, McKinney JD (2010) Mycobacterium tuberculosis persistence mutants identified by screening in isoniazid-treated mice. Proc National Acad Sci USA 107:12275–12280

    CAS  Google Scholar 

  • Dorman SE, Chaisson RE (2007) From magic bullets back to the magic mountain: the rise of extensively drug-resistant tuberculosis. Nat Med 13:295–298

    PubMed  CAS  Google Scholar 

  • Duncan K, Barry CE 3rd (2004) Prospects for new antitubercular drugs. Curr Opin Microbiol 7:460–465

    PubMed  CAS  Google Scholar 

  • 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 66:1247–1254

    PubMed  Google Scholar 

  • Ferber D (2005) Biochemistry. Protein that mimics DNA helps tuberculosis bacteria resist antibiotics. Science 308:1393

    Google Scholar 

  • Flores AR, Parsons LM, Pavelka MS Jr (2005) Genetic analysis of the beta-lactamases of Mycobacterium tuberculosis and Mycobacterium smegmatis and susceptibility to beta-lactam antibiotics. Microbiology 151:521–532

    PubMed  CAS  Google Scholar 

  • Gagneux S, Long CD, Small PM, Van T, Schoolnik GK, Bohannan BJ (2006) The competitive cost of antibiotic resistance in Mycobacterium tuberculosis. Science 312:1944–1946

    PubMed  CAS  Google Scholar 

  • 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 49:1547–1563

    PubMed  CAS  Google Scholar 

  • Garton NJ, Waddell SJ, Sherratt AL et al (2008) Cytological and transcript analyses reveal fat and lazy persister-like bacilli in tuberculous sputum. PLoS medicine 5:e75

    PubMed  Google Scholar 

  • Gengenbacher M, Kaufmann SH (2012) Mycobacterium tuberculosis: success through dormancy. FEMS Microbiol Rev 36:514–532

    PubMed  CAS  Google Scholar 

  • Gillespie SH, Billington OJ, Breathnach A, McHugh TD (2002) Multiple drug-resistant Mycobacterium tuberculosis: evidence for changing fitness following passage through human hosts. Microbial Drug Resist 8:273–279

    Google Scholar 

  • Gomez JE, McKinney JD (2004) M. tuberculosis persistence, latency, and drug tolerance. Tuberculosis 84:29–44

    PubMed  Google Scholar 

  • Han JS, Lee JJ, Anandan T et al (2010) Characterization of a chromosomal toxin-antitoxin, Rv1102c-Rv1103c system in Mycobacterium tuberculosis. Biochemical Biophys Res Commun 400:293–298

    CAS  Google Scholar 

  • Hansen S, Lewis K, Vulic M (2008) Role of global regulators and nucleotide metabolism in antibiotic tolerance in Escherichia coli. Antimicrobial Agents Chemother 52:2718–2726

    CAS  Google Scholar 

  • Hegde SS, Vetting MW, Roderick SL, Mitchenall LA, Maxwell A, Takiff HE, Blanchard JS (2005) A fluoroquinolone resistance protein from Mycobacterium tuberculosis that mimics DNA. Science 308:1480–1483

    PubMed  CAS  Google Scholar 

  • 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: MMBR 66:373–395

    PubMed  CAS  Google Scholar 

  • 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 105:3963–3967

    PubMed  CAS  Google Scholar 

  • 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 49:2502–2508

    PubMed  Google Scholar 

  • Hugonnet JE, Blanchard JS (2007) Irreversible inhibition of the Mycobacterium tuberculosis beta-lactamase by clavulanate. Biochemistry 46:11998–12004

    PubMed  CAS  Google Scholar 

  • 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 31:11606–11613

    PubMed  CAS  Google Scholar 

  • Jarlier V, Gutmann L, Nikaido H (1991) Interplay of cell wall barrier and beta-lactamase activity determines high resistance to beta-lactam antibiotics in Mycobacterium chelonae. Antimicrob Agents Chemother 35:1937–1939

    PubMed  CAS  Google Scholar 

  • 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 23:173–182

    PubMed  CAS  Google Scholar 

  • Kasik JE (1979) Mycobacterial Beta-Lactamases. In: Hamilton-Miller JMT, Smith JT (eds) Beta-Lactamases. Academic Press, London, p 500

    Google Scholar 

  • Kasik JE, Peacham L (1968) Properties of beta-lactamases produced by three species of mycobacteria. Biochem J 107:675–682

    PubMed  CAS  Google Scholar 

  • Keiler KC (2008) Biology of trans-translation. Annual Rev Microbiol 62:133–151

    CAS  Google Scholar 

  • Keren I, Minami S, Rubin E, Lewis K (2011) Characterization and transcriptome analysis of Mycobacterium tuberculosis persisters. mBio 2:e00100-00111

    Google Scholar 

  • 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 186:8172–8180

    PubMed  CAS  Google Scholar 

  • Kohanski MA, DePristo MA, Collins JJ (2010a) Sublethal antibiotic treatment leads to multidrug resistance via radical-induced mutagenesis. Mol Cell 37:311–320

    PubMed  CAS  Google Scholar 

  • Kohanski MA, Dwyer DJ, Collins JJ (2010b) How antibiotics kill bacteria: from targets to networks. Nat Rev Microbiol 8:423–435

    PubMed  CAS  Google Scholar 

  • Kohanski MA, Dwyer DJ, Hayete B, Lawrence CA, Collins JJ (2007) A common mechanism of cellular death induced by bactericidal antibiotics. Cell 130:797–810

    PubMed  CAS  Google Scholar 

  • Lewis K (2008) Multidrug tolerance of biofilms and persister cells. Curr Top Microbiol Immunol 322:107–131

    PubMed  CAS  Google Scholar 

  • Li Y, Zhang Y (2007) PhoU is a persistence switch involved in persister formation and tolerance to multiple antibiotics and stresses in Escherichia coli. Antimicrobial Agents Chemother 51:2092–2099

    CAS  Google Scholar 

  • Liu J, Nikaido H (1999) A mutant of Mycobacterium smegmatis defective in the biosynthesis of mycolic acids accumulates meromycolates. Proc Natl Acad Sci U S A 96:4011–4016

    PubMed  CAS  Google Scholar 

  • Liu J, Rosenberg EY, Nikaido H (1995) Fluidity of the lipid domain of cell wall from Mycobacterium chelonae. Proc Natl Acad Sci USA 92:11254–11258

    PubMed  CAS  Google Scholar 

  • 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 280:38942–38947

    PubMed  CAS  Google Scholar 

  • Maus CE, Plikaytis BB, Shinnick TM (2005) Mutation of tlyA confers capreomycin resistance in Mycobacterium tuberculosis. Antimicrobial Agents Chemother 49:571–577

    CAS  Google Scholar 

  • 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 104:763–802

    PubMed  CAS  Google Scholar 

  • 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 104:737–762

    PubMed  CAS  Google Scholar 

  • 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 194:2189–2204

    PubMed  CAS  Google Scholar 

  • Michele TM, Ko C, Bishai WR (1999) Exposure to antibiotics induces expression of the Mycobacterium tuberculosis sigF gene: implications for chemotherapy against mycobacterial persistors. Antimicrobial Agents Chemother 43:218–225

    CAS  Google Scholar 

  • 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 45:3387–3392

    PubMed  CAS  Google Scholar 

  • 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 388:903–906

    PubMed  CAS  Google Scholar 

  • Morris RP, Nguyen L, Gatfield J et al (2005) Ancestral antibiotic resistance in Mycobacterium tuberculosis. Proc Natl Acad Sci USA 102:12200–12205

    PubMed  CAS  Google Scholar 

  • Myers A (1963) Can tuberculosis be eradicated? Chest 43:327–329

    CAS  Google Scholar 

  • Nampoothiri KM, Rubex R, Patel AK, Narayanan SS, Krishna S, Das SM, Pandey A (2008) Molecular cloning, overexpression and biochemical characterization of hypothetical beta-lactamases of Mycobacterium tuberculosis H37Rv. J Appl Microbiol 105:59–67

    PubMed  CAS  Google Scholar 

  • Nash KA (2003) Intrinsic macrolide resistance in Mycobacterium smegmatis is conferred by a novel erm gene, erm(38). Antimicrob Agents Chemother 47:3053–3060

    PubMed  CAS  Google Scholar 

  • 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 55:170–177

    PubMed  CAS  Google Scholar 

  • Nguyen L (2012) Targeting antibiotic resistance mechanisms in Mycobacterium tuberculosis: recharging the old magic bullets. Expert Rev Anti Infect Ther 10:963–965

    Google Scholar 

  • 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 187:6603–6611

    PubMed  CAS  Google Scholar 

  • Nguyen L, Pieters J (2009) Mycobacterial subversion of chemotherapeutic reagents and host defense tactics: challenges in tuberculosis drug development. Ann Rev Pharmacol Toxicol 49:427–453

    CAS  Google Scholar 

  • 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 281:12300–12307

    PubMed  CAS  Google Scholar 

  • Niederweis M (2003) Mycobacterial porins-new channel proteins in unique outer membranes. Mol Microbiol 49:1167–1177

    PubMed  CAS  Google Scholar 

  • Nikaido H (1994) Prevention of drug access to bacterial targets: permeability barriers and active efflux. Science 264:382–388

    PubMed  CAS  Google Scholar 

  • Nishino K, Yamaguchi A (2001) Analysis of a complete library of putative drug transporter genes in Escherichia coli. J Bacteriol 183:5803–5812

    PubMed  CAS  Google Scholar 

  • Nott TJ, Kelly G, Stach L, et al (2009) An intramolecular switch regulates phosphoindependent FHA domain interactions in Mycobacterium tuberculosis. Science Signal 2:ra12

    Google Scholar 

  • Ormerod LP (2005) Multidrug-resistant tuberculosis (MDR-TB): epidemiology, prevention and treatment. Br Med Bull 73–74:17–24

    PubMed  Google Scholar 

  • Philalay JS, Palermo CO, Hauge KA, Rustad TR, Cangelosi GA (2004) Genes required for intrinsic multidrug resistance in Mycobacterium avium. Antimicrob Agents Chemother 48:3412–3418

    PubMed  CAS  Google Scholar 

  • Quinting B, Reyrat JM, Monnaie D et al (1997) Contribution of beta-lactamase production to the resistance of mycobacteria to beta-lactam antibiotics. FEBS Lett 406:275–278

    PubMed  CAS  Google Scholar 

  • 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 46:3348–3355

    PubMed  CAS  Google Scholar 

  • Reynolds MG (2000) Compensatory evolution in rifampin-resistant Escherichia coli. Genetics 156:1471–1481

    PubMed  CAS  Google Scholar 

  • 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 35:2368–2376

    Google Scholar 

  • Sala C, Haouz A, Saul FA, Miras I, Rosenkrands I, Alzari PM, Cole ST (2009) Genome-wide regulon and crystal structure of BlaI (Rv1846c) from Mycobacterium tuberculosis. Mol Microbiol 71:1102–1116

    PubMed  CAS  Google Scholar 

  • 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 67:4531–4538

    PubMed  CAS  Google Scholar 

  • Scorpio A, Lindholm-Levy P, Heifets L, Gilman R, Siddiqi S, Cynamon M, Zhang Y (1997) Characterization of pncA mutations in pyrazinamide-resistant Mycobacterium tuberculosis. Antimicrobial Agents Chemother 41:540–543

    CAS  Google Scholar 

  • 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 2:662–667

    PubMed  CAS  Google Scholar 

  • 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 180:3541–3547

    PubMed  CAS  Google Scholar 

  • 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 4:135ra167

    Google Scholar 

  • 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 287:12835–12847

    PubMed  CAS  Google Scholar 

  • Sherman DR, Mdluli K, Hickey MJ, Arain TM, Morris SL, Barry CE 3rd, Stover CK (1996) Compensatory ahpC gene expression in isoniazid-resistant Mycobacterium tuberculosis. Science 272:1641–1643

    PubMed  CAS  Google Scholar 

  • Shi L, Sohaskey CD, Kana BD, Dawes S, North RJ, Mizrahi V, Gennaro ML (2005) Changes in energy metabolism of Mycobacterium tuberculosis in mouse lung and under in vitro conditions affecting aerobic respiration. Proc Natl Acad Sci USA 102:15629–15634

    PubMed  CAS  Google Scholar 

  • Shi W, Zhang X, Jiang X et al (2011) Pyrazinamide inhibits trans-translation in Mycobacterium tuberculosis. Science 333:1630–1632

    PubMed  CAS  Google Scholar 

  • Shi W, Zhang Y (2010) PhoY2 but not PhoY1 is the PhoU homologue involved in persisters in Mycobacterium tuberculosis. J Antimicrob Chemother 65:1237–1242

    PubMed  CAS  Google Scholar 

  • Shiba T, Tsutsumi K, Yano H et al (1997) Inorganic polyphosphate and the induction of rpoS expression. Proc Natl Acad Sci USA 94:11210–11215

    PubMed  CAS  Google Scholar 

  • Singh A, Gupta R, Vishwakarma RA, Narayanan PR, Paramasivan CN, Ramanathan VD, Tyagi AK (2005) Requirement of the mymA operon for appropriate cell wall ultrastructure and persistence of Mycobacterium tuberculosis in the spleens of guinea pigs. J Bacteriol 187:4173–4186

    PubMed  CAS  Google Scholar 

  • 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 227:53–63

    PubMed  CAS  Google Scholar 

  • 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 283:17827–17837

    PubMed  CAS  Google Scholar 

  • Stephan J, Mailaender C, Etienne G, Daffe M, Niederweis M (2004) Multidrug resistance of a porin deletion mutant of Mycobacterium smegmatis. Antimicrob Agents Chemother 48:4163–4170

    PubMed  CAS  Google Scholar 

  • 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:e28076

    PubMed  CAS  Google Scholar 

  • Tian J, Bryk R, Itoh M, Suematsu M, Nathan C (2005) Variant tricarboxylic acid cycle in Mycobacterium tuberculosis: identification of alpha-ketoglutarate decarboxylase. Proc Natl Acad Sci USA 102:10670–10675

    PubMed  CAS  Google Scholar 

  • Tremblay LW, Fan F, Blanchard JS (2010) Biochemical and structural characterization of Mycobacterium tuberculosis beta-lactamase with the carbapenems ertapenem and doripenem. Biochemistry 49:3766–3773

    PubMed  CAS  Google Scholar 

  • Udwadia ZF (2012) MDR, XDR, TDR tuberculosis: ominous progression. Thorax 67:286–288

    PubMed  Google Scholar 

  • Vetting M, Roderick SL, Hegde S, Magnet S, Blanchard JS (2003) What can structure tell us about in vivo function? The case of aminoglycoside-resistance genes. Biochem Soc Trans 31:520–522

    PubMed  CAS  Google Scholar 

  • Vilcheze C, Av-Gay Y, Attarian R et al (2008) Mycothiol biosynthesis is essential for ethionamide susceptibility in Mycobacterium tuberculosis. Molec Microbiol 69:1316–1329

    CAS  Google Scholar 

  • Viveirosa M, Martins M, Rodrigues L, Machado D, Coutoa I, Ainsad J, Amaral L (2012) Inhibitors of mycobacterial efflux pumps as potential boosters for TB drugs. Expert Rev Anti Infect Ther 10:983–998

    Google Scholar 

  • Voladri RK, Lakey DL, Hennigan SH, Menzies BE, Edwards KM, Kernodle DS (1998) Recombinant expression and characterization of the major beta-lactamase of Mycobacterium tuberculosis. Antimicrob Agents Chemother 42:1375–1381

    PubMed  CAS  Google Scholar 

  • Walburger A, Koul A, Ferrari G et al (2004) Protein kinase G from pathogenic mycobacteria promotes survival within macrophages. Science 304:1800–1804

    PubMed  CAS  Google Scholar 

  • Wallis RS, Patil S, Cheon SH et al (1999) Drug tolerance in Mycobacterium tuberculosis. Antimicrobial Agents Chemother 43:2600–2606

    CAS  Google Scholar 

  • Wang F, Cassidy C, Sacchettini JC (2006) Crystal structure and activity studies of the Mycobacterium tuberculosis beta-lactamase reveal its critical role in resistance to beta-lactam antibiotics. Antimicrob Agents Chemother 50:2762–2771

    PubMed  CAS  Google Scholar 

  • Wang JY, Burger RM, Drlica K (1998) Role of superoxide in catalase-peroxidase-mediated isoniazid action against mycobacteria. Antimicrobial Agents Chemother 42:709–711

    CAS  Google Scholar 

  • Wang X, Mitra N, Secundino I et al (2012) Specific inactivation of two immunomodulatory SIGLEC genes during human evolution. Proc Natl Acad Sci USA 109:9935–9940

    PubMed  CAS  Google Scholar 

  • 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 73:134–136

    PubMed  CAS  Google Scholar 

  • 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 64:2062–2069

    PubMed  CAS  Google Scholar 

  • Wei J, Dahl JL, Moulder JW, Roberts EA, O’Gaora P, Young DB, Friedman RL (2000) Identification of a Mycobacterium tuberculosis gene that enhances mycobacterial survival in macrophages. J Bacteriol 182:377–384

    PubMed  CAS  Google Scholar 

  • Wolff KA, Nguyen HT, Cartabuke RH, Singh A, Ogwang S, Nguyen L (2009) Protein kinase G is required for intrinsic antibiotic resistance in mycobacteria. Antimicrobial Agents Chemother 53:3515–3519

    CAS  Google Scholar 

  • 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 19:6612–6621

    PubMed  CAS  Google Scholar 

  • Xie Z, Siddiqi N, Rubin EJ (2005) Differential antibiotic susceptibilities of starved Mycobacterium tuberculosis isolates. Antimicrobial Agents Chemother 49:4778–4780

    CAS  Google Scholar 

  • 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 106:20004–20009

    PubMed  CAS  Google Scholar 

  • Zhang Y (2012) Drug resistant and persistent tuberculosis: mechanisms and drug development. In: Dougherty TJ, Pucci MJ (ed) Antibiotic discovery and development. Springer Science + Business Media, pp 719–746

    Google Scholar 

  • Zhang Y, Dhandayuthapani S, Deretic V (1996) Molecular basis for the exquisite sensitivity of Mycobacterium tuberculosis to isoniazid. Proc Natl Acad Sci USA 93:13212–13216

    PubMed  CAS  Google Scholar 

  • Zhang Y, Heym B, Allen B, Young D, Cole S (1992) The catalase-peroxidase gene and isoniazid resistance of Mycobacterium tuberculosis. Nature 358:591–593

    PubMed  CAS  Google Scholar 

  • 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 190:5672–5680

    PubMed  CAS  Google Scholar 

Download references

Acknowledgments

Work in the Nguyen laboratory is supported by NIH Grant R01 AI087903.

Author information

Authors and Affiliations

  1. Case Western Reserve University School of Medicine, Cleveland, OH, 44106, USA

    Tasha Smith & Kerstin A. Wolff

  2. Department of Molecular Biology and Microbiology, School of Medicine, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, OH, 44106-4960, USA

    Liem Nguyen

Authors
  1. Tasha Smith
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Kerstin A. Wolff
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Liem Nguyen
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Liem Nguyen .

Editor information

Editors and Affiliations

  1. Biozentrum, University of Basel, Basel, Switzerland

    Jean Pieters

  2. Laboratory of Microbiology and Microsystems, Swiss Federal Institute of Technology Lausanne (EPFL), Lausanne, Switzerland

    John D. McKinney

Rights and permissions

Reprints and permissions

Copyright information

© 2012 Springer-Verlag Berlin Heidelberg

About this chapter

Cite this chapter

Smith, T., Wolff, K.A., Nguyen, L. (2012). Molecular Biology of Drug Resistance in Mycobacterium tuberculosis . In: Pieters, J., McKinney, J. (eds) Pathogenesis of Mycobacterium tuberculosis and its Interaction with the Host Organism. Current Topics in Microbiology and Immunology, vol 374. Springer, Berlin, Heidelberg. https://doi.org/10.1007/82_2012_279

Download citation

Publish with us

Policies and ethics

Search

Navigation