Antimicrobial Efflux Pumps and Mycobacterium tuberculosis Drug Tolerance: Evolutionary Considerations

  • John D. Szumowski
  • Kristin N. Adams
  • Paul H. Edelstein
  • Lalita Ramakrishnan
Chapter

Abstract

The need for lengthy treatment to cure tuberculosis stems from phenotypic drug resistance, also known as drug tolerance, which has been previously attributed to slowed bacterial growth in vivo. We discuss recent findings that challenge this model and instead implicate macrophage-induced mycobacterial efflux pumps in antimicrobial tolerance. Although mycobacterial efflux pumps may have originally served to protect against environmental toxins, in the pathogenic mycobacteria, they appear to have been repurposed for intracellular growth. In this light, we discuss the potential of efflux pump inhibitors such as verapamil to shorten tuberculosis treatment by their dual inhibition of tolerance and growth.

References

  1. Adams KN, Takaki K, Connolly LE, Wiedenhoft H, Winglee K, Humbert O, Edelstein PH, Cosma CL, Ramakrishnan L (2011) Drug tolerance in replicating mycobacteria mediated by a macrophage-induced efflux mechanism. Cell 145:39–53. doi:10.1016/j.cell.2011.02.022 PubMedGoogle Scholar
  2. Aeschlimann JR, Kaatz GW, Rybak MJ (1999) The effects of NorA inhibition on the activities of levofloxacin, ciprofloxacin and norfloxacin against two genetically related strains of Staphylococcus aureus in an in vitro infection model. J Antimicrob Chemother 44:343–349PubMedGoogle Scholar
  3. Ahmed M, Borsch CM, Neyfakh AA, Schuldiner S (1993) Mutants of the Bacillus subtilis multidrug transporter Bmr with altered sensitivity to the antihypertensive alkaloid reserpine. J Biol Chem 268:11086–11089PubMedGoogle Scholar
  4. 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 180:5836–5843PubMedGoogle Scholar
  5. Akira M, Sakatani M, Ishikawa H (2000) Transient radiographic progression during initial treatment of pulmonary tuberculosis: CT findings. J Comput Assist Tomogr 24:426–431PubMedGoogle Scholar
  6. Amaral L, Boeree MJ, Gillespie SH, Udwadia ZF, van Soolingen D (2010) Thioridazine cures extensively drug-resistant tuberculosis (XDR-TB) and the need for global trials is now! Int J Antimicrob Agents 35:524–526. doi:10.1016/j.ijantimicag.2009.12.019 PubMedGoogle Scholar
  7. Asaduzzaman SM, Sonomoto K (2009) Lantibiotics: diverse activities and unique modes of action. J Biosci Bioeng 107:475–487. doi:10.1016/j.jbiosc.2009.01.003 PubMedGoogle Scholar
  8. Balganesh M, Dinesh N, Sharma S, Kuruppath S, Nair AV, Sharma U (2012) Efflux pumps of Mycobacterium tuberculosis Play a significant role in antituberculosis activity of potential drug candidates. Antimicrob Agents Chemother 56:2643–2651. doi:10.1128/AAC.06003-11 PubMedGoogle Scholar
  9. Balganesh M, Kuruppath S, Marcel N, Sharma S, Nair A, Sharma U (2010) Rv1218c, an ABC transporter of Mycobacterium tuberculosis with implications in drug discovery. Antimicrob Agents Chemother 54:5167–5172. doi:10.1128/AAC.00610-10 PubMedGoogle Scholar
  10. Ball PR, Shales SW, Chopra I (1980) Plasmid-mediated tetracycline resistance in Escherichia coli involves increased efflux of the antibiotic. Biochem Biophys Res Commun 93:74–81PubMedGoogle Scholar
  11. Barker J, Scaife H, Brown MR (1995) Intraphagocytic growth induces an antibiotic-resistant phenotype of Legionella pneumophila. Antimicrob Agents Chemother 39:2684–2688PubMedGoogle Scholar
  12. Bayer AS, Kupferwasser LI, Brown MH, Skurray RA, Grkovic S, Jones T, Mukhopadhay K, Yeaman MR (2006) Low-level resistance of Staphylococcus aureus to thrombin-induced platelet microbicidal protein 1 in vitro associated with qacA gene carriage is independent of multidrug efflux pump activity. Antimicrob Agents Chemother 50:2448–2454. doi:10.1128/AAC.00028-06 PubMedGoogle Scholar
  13. Bengoechea JA, Skurnik M (2000) Temperature-regulated efflux pump/potassium antiporter system mediates resistance to cationic antimicrobial peptides in yersinia. Mol Microbiol 37:67–80PubMedGoogle Scholar
  14. Beumer A, King D, Donohue M, Mistry J, Covert T, Pfaller S (2010) Detection of Mycobacterium avium subsp. paratuberculosis in drinking water and biofilms by quantitative PCR. Appl Environ Microbiol 76:7367–7370. doi:10.1128/AEM.00730-10 PubMedGoogle Scholar
  15. Bianco MV, Blanco FC, Imperiale B, Forrellad MA, Rocha RV, Klepp LI, Cataldi AA, Morcillo N, Bigi F (2011) Role of P27–P55 operon from Mycobacterium tuberculosis in the resistance to toxic compounds. BMC Infect Dis 11:195. doi:10.1186/1471-2334-11-195 PubMedGoogle Scholar
  16. Biet F, Boschiroli ML, Thorel MF, Guilloteau LA (2005) Zoonotic aspects of Mycobacterium bovis and Mycobacterium avium-intracellulare complex (MAC). Vet Res 36:411–436. doi:10.1051/vetres:2005001 PubMedGoogle Scholar
  17. Bigger J (1944) Treatment of staphylococcal infections with penicillin. Lancet 244:497–500Google Scholar
  18. Bigi F, Gioffre A, Klepp L, Santangelo MP, Alito A, Caimi K, Meikle V, Zumarraga M, Taboga O, Romano MI, Cataldi A (2004) The knockout of the lprG-Rv1410 operon produces strong attenuation of Mycobacterium tuberculosis. Microbes Infect Inst Pasteur 6:182–187. doi:10.1016/j.micinf.2003.10.010 Google Scholar
  19. Bina XR, Lavine CL, Miller MA, Bina JE (2008a) The AcrAB RND efflux system from the live vaccine strain of Francisella tularensis is a multiple drug efflux system that is required for virulence in mice. FEMS Microbiol Lett 279:226–233. doi:10.1111/j.1574-6968.2007.01033.x PubMedGoogle Scholar
  20. Bina XR, Provenzano D, Nguyen N, Bina JE (2008b) Vibrio cholerae RND family efflux systems are required for antimicrobial resistance, optimal virulence factor production, and colonization of the infant mouse small intestine. Infect Immun 76:3595–3605. doi:10.1128/IAI.01620-07 PubMedGoogle Scholar
  21. Blair JM, Piddock LJ (2009) Structure, function and inhibition of RND efflux pumps in Gram-negative bacteria: an update. Curr Opin Microbiol 12:512–519. doi:10.1016/j.mib.2009.07.003 PubMedGoogle Scholar
  22. Bobrowitz ID (1980) Reversible roentgenographic progression in the initial treatment of pulmonary tuberculosis. Am Rev Respir Dis 121:735–742PubMedGoogle Scholar
  23. Braibant M, Gilot P, Content J (2000) The ATP binding cassette (ABC) transport systems of Mycobacterium tuberculosis. FEMS Microbiol Rev 24:449–467PubMedGoogle Scholar
  24. Brissette CA, Lukehart SA (2007) Mechanisms of decreased susceptibility to beta-defensins by Treponema denticola. Infect Immun 75:2307–2315. doi:10.1128/IAI.01718-06 PubMedGoogle Scholar
  25. Buckley AM, Webber MA, Cooles S, Randall LP, La Ragione RM, Woodward MJ, Piddock LJ (2006) The AcrAB-TolC efflux system of Salmonella enterica serovar Typhimurium plays a role in pathogenesis. Cell Microbiol 8:847–856. doi:10.1111/j.1462-5822.2005.00671.x PubMedGoogle Scholar
  26. Bunikis I, Denker K, Ostberg Y, Andersen C, Benz R, Bergstrom S (2008) An RND-type efflux system in Borrelia burgdorferi is involved in virulence and resistance to antimicrobial compounds. PLoS Pathog 4:e1000009. doi:10.1371/journal.ppat.1000009 PubMedGoogle Scholar
  27. Camacho LR, Constant P, Raynaud C, Laneelle MA, Triccas JA, Gicquel B, Daffe M, Guilhot C (2001) Analysis of the phthiocerol dimycocerosate locus of Mycobacterium tuberculosis. Evidence that this lipid is involved in the cell wall permeability barrier. J Biol Chem 276:19845–19854. doi:10.1074/jbc.M100662200 PubMedGoogle Scholar
  28. Camus JC, Pryor MJ, Medigue C, Cole ST (2002) Re-annotation of the genome sequence of Mycobacterium tuberculosis H37Rv. Microbiology 148:2967–2973PubMedGoogle Scholar
  29. Canetti G (1955) The tubercle bacillus in the pulmonary lesion of man, histobacteriology and its bearing on the therapy of pulmonary tuberculosis. Springer, New YorkGoogle Scholar
  30. Cao CX, Silverstein SC, Neu HC, Steinberg TH (1992) J774 macrophages secrete antibiotics via organic anion transporters. J Infect Dis 165:322–328PubMedGoogle Scholar
  31. Castelnuovo B (2010) A review of compliance to anti tuberculosis treatment and risk factors for defaulting treatment in Sub Saharan Africa. Afr Health Sci 10:320–324PubMedGoogle Scholar
  32. Chan K, Knaak T, Satkamp L, Humbert O, Falkow S, Ramakrishnan L (2002) Complex pattern of Mycobacterium marinum gene expression during long-term granulomatous infection. Proc Natl Acad Sci U S A 99:3920–3925. doi:10.1073/pnas.002024599 PubMedGoogle Scholar
  33. Chan YY, Chua KL (2005) The Burkholderia pseudomallei BpeAB-OprB efflux pump: expression and impact on quorum sensing and virulence. J Bacteriol 187:4707–4719. doi:10.1128/JB.187.14.4707-4719.2005 PubMedGoogle Scholar
  34. Chauty A, Ardant MF, Adeye A, Euverte H, Guedenon A, Johnson C, Aubry J, Nuermberger E, Grosset J (2007) Promising clinical efficacy of streptomycin-rifampin combination for treatment of buruli ulcer (Mycobacterium ulcerans disease). Antimicrob Agents Chemother 51:4029–4035. doi:10.1128/AAC.00175-07 PubMedGoogle Scholar
  35. Choudhuri BS, Bhakta S, Barik R, Basu J, Kundu M, Chakrabarti P (2002) Overexpression and functional characterization of an ABC (ATP-binding cassette) transporter encoded by the genes drrA and drrB of Mycobacterium tuberculosis. Biochem J 367:279–285. doi:10.1042/BJ20020615 PubMedGoogle Scholar
  36. Clay H, Davis JM, Beery D, Huttenlocher A, Lyons SE, Ramakrishnan L (2007) Dichotomous role of the macrophage in early Mycobacterium marinum infection of the zebrafish. Cell Host Microbe 2:29–39. doi:10.1016/j.chom.2007.06.004 PubMedGoogle Scholar
  37. Colangeli R, Helb D, Sridharan S, Sun J, Varma-Basil M, Hazbon MH, Harbacheuski R, Megjugorac NJ, Jacobs WR Jr, Holzenburg A, Sacchettini JC, Alland D (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. doi:10.1111/j.1365-2958.2005.04510.x PubMedGoogle Scholar
  38. Cole ST, Brosch R, Parkhill J, Garnier T, Churcher C, Harris D, Gordon SV, Eiglmeier K, Gas S, Barry CE 3rd, Tekaia F, Badcock K, Basham D, Brown D, Chillingworth T, Connor R, Davies R, Devlin K, Feltwell T, Gentles S, Hamlin N, Holroyd S, Hornsby T, Jagels K, Krogh A, McLean J, Moule S, Murphy L, Oliver K, Osborne J, Quail MA, Rajandream MA, Rogers J, Rutter S, Seeger K, Skelton J, Squares R, Squares S, Sulston JE, Taylor K, Whitehead S, Barrell BG (1998) Deciphering the biology of Mycobacterium tuberculosis from the complete genome sequence. Nature 393:537–544. doi:10.1038/31159 PubMedGoogle Scholar
  39. Cole ST, Eiglmeier K, Parkhill J, James KD, Thomson NR, Wheeler PR, Honore N, Garnier T, Churcher C, Harris D, Mungall K, Basham D, Brown D, Chillingworth T, Connor R, Davies RM, Devlin K, Duthoy S, Feltwell T, Fraser A, Hamlin N, Holroyd S, Hornsby T, Jagels K, Lacroix C, Maclean J, Moule S, Murphy L, Oliver K, Quail MA, Rajandream MA, Rutherford KM, Rutter S, Seeger K, Simon S, Simmonds M, Skelton J, Squares R, Squares S, Stevens K, Taylor K, Whitehead S, Woodward JR, Barrell BG (2001) Massive gene decay in the leprosy bacillus. Nature 409:1007–1011. doi:10.1038/35059006 PubMedGoogle Scholar
  40. Connolly LE, Edelstein PH, Ramakrishnan L (2007) Why is long-term therapy required to cure tuberculosis? PLoS Med 4:e120. doi:10.1371/journal.pmed.0040120 PubMedGoogle Scholar
  41. East African/British Medical Research Councils (1972) Controlled clinical trial of short-course (6-month) regimens of chemotherapy for treatment of pulmonary tuberculosis. Lancet 1:1079–1085 Google Scholar
  42. Hong Kong Chest Service/Tuberculosis Research Centre, Madras/British Medical Research Council (1989) A controlled trial of 3-month, 4-month, and 6-month regimens of chemotherapy for sputum-smear-negative pulmonary tuberculosis. Results at 5 years. Am Rev Respir Dis 139:871–876Google Scholar
  43. Cosma CL, Humbert O, Ramakrishnan L (2004) Superinfecting mycobacteria home to established tuberculous granulomas. Nat Immunol 5:828–835. doi:10.1038/ni1091 PubMedGoogle Scholar
  44. Cosma CL, Sherman DR, Ramakrishnan L (2003) The secret lives of the pathogenic mycobacteria. Annu Rev Microbiol 57:641–676. doi:10.1146/annurev.micro.57.030502.091033 PubMedGoogle Scholar
  45. Cox JS, Chen B, McNeil M, Jacobs WR Jr (1999) Complex lipid determines tissue-specific replication of Mycobacterium tuberculosis in mice. Nature 402:79–83. doi:10.1038/47042 PubMedGoogle Scholar
  46. Coyne S, Courvalin P, Perichon B (2011) Efflux-mediated antibiotic resistance in Acinetobacter spp. Antimicrob Agents Chemother 55:947–953. doi:10.1128/AAC.01388-10 PubMedGoogle Scholar
  47. Crimmins GT, Herskovits AA, Rehder K, Sivick KE, Lauer P, Dubensky TW Jr, Portnoy DA (2008) Listeria monocytogenes multidrug resistance transporters activate a cytosolic surveillance pathway of innate immunity. Proc Natl Acad Sci U S A 105:10191–10196. doi:10.1073/pnas.0804170105 PubMedGoogle Scholar
  48. Curry JM, Whalan R, Hunt DM, Gohil K, Strom M, Rickman L, Colston MJ, Smerdon SJ, Buxton RS (2005) An ABC transporter containing a forkhead-associated domain interacts with a serine-threonine protein kinase and is required for growth of Mycobacterium tuberculosis in mice. Infect Immun 73:4471–4477. doi:10.1128/IAI.73.8.4471-4477.2005 PubMedGoogle Scholar
  49. 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. doi:10.1111/j.1574-695X.2011.00831.x PubMedGoogle Scholar
  50. Danilchanka O, Mailaender C, Niederweis M (2008) Identification of a novel multidrug efflux pump of Mycobacterium tuberculosis. Antimicrob Agents Chemother 52:2503–2511. doi:10.1128/AAC.00298-08 PubMedGoogle Scholar
  51. Dannenberg AM Jr (1993) Immunopathogenesis of pulmonary tuberculosis. Hospital Practice 28:51–58PubMedGoogle Scholar
  52. Dannenberg AM Jr (2003) Macrophage turnover, division and activation within developing, peak and “healed” tuberculous lesions produced in rabbits by BCG. Tuberculosis 83:251–260PubMedGoogle Scholar
  53. De Rossi E, Arrigo P, Bellinzoni M, Silva PA, Martin C, Ainsa JA, Guglierame P, Riccardi G (2002) The multidrug transporters belonging to major facilitator superfamily in Mycobacterium tuberculosis. Mol Med 8:714–724PubMedGoogle Scholar
  54. DeMarco CE, Cushing LA, Frempong-Manso E, Seo SM, Jaravaza TA, Kaatz GW (2007) Efflux-related resistance to norfloxacin, dyes, and biocides in bloodstream isolates of Staphylococcus aureus. Antimicrob Agents Chemother 51:3235–3239. doi:10.1128/AAC.00430-07 PubMedGoogle Scholar
  55. Dhar N, McKinney JD (2007) Microbial phenotypic heterogeneity and antibiotic tolerance. Curr Opin Microbiol 10:30–38. doi:10.1016/j.mib.2006.12.007 PubMedGoogle Scholar
  56. Dhawan VK, Yeaman MR, Cheung AL, Kim E, Sullam PM, Bayer AS (1997) Phenotypic resistance to thrombin-induced platelet microbicidal protein in vitro is correlated with enhanced virulence in experimental endocarditis due to Staphylococcus aureus. Infect Immun 65:3293–3299PubMedGoogle Scholar
  57. Dianiskova P, Kordulakova J, Skovierova H, Kaur D, Jackson M, Brennan PJ, Mikusova K (2011) Investigation of ABC transporter from mycobacterial arabinogalactan biosynthetic cluster. Gen Physiol Biophys 30:239–250. doi:10.4149/gpb_2011_03_239Google Scholar
  58. Ding Y, Onodera Y, Lee JC, Hooper DC (2008) NorB, an efflux pump in Staphylococcus aureus strain MW2, contributes to bacterial fitness in abscesses. J Bacteriol 190:7123–7129. doi:10.1128/JB.00655-08 PubMedGoogle Scholar
  59. Djoko KY, Franiek JA, Edwards JL, Falsetta ML, Kidd SP, Potter AJ, Chen NH, Apicella MA, Jennings MP, McEwan AG (2012) Phenotypic characterization of a copA mutant of Neisseria gonorrhoeae identifies a link between copper and nitrosative stress. Infect Immun 80:1065–1071. doi:10.1128/IAI.06163-11 PubMedGoogle Scholar
  60. Doig KD, Holt KE, Fyfe JA, Lavender CJ, Eddyani M, Portaels F, Yeboah-Manu D, Pluschke G, Seemann T, Stinear TP (2012) On the origin of Mycobacterium ulcerans, the causative agent of buruli ulcer. BMC Genomics 13:258. doi:10.1186/1471-2164-13-258 PubMedGoogle Scholar
  61. Domenech P, Reed MB, Barry CE 3rd (2005) Contribution of the Mycobacterium tuberculosis MmpL protein family to virulence and drug resistance. Infect Immun 73:3492–3501. doi:10.1128/IAI.73.6.3492-3501.2005 PubMedGoogle Scholar
  62. Duits LA, Rademaker M, Ravensbergen B, van Sterkenburg MA, van Strijen E, Hiemstra PS, Nibbering PH (2001) Inhibition of hBD-3, but not hBD-1 and hBD-2, mRNA expression by corticosteroids. Biochem Biophys Res Commun 280:522–525. doi:10.1006/bbrc.2000.4157 PubMedGoogle Scholar
  63. Ehrchen J, Steinmuller L, Barczyk K, Tenbrock K, Nacken W, Eisenacher M, Nordhues U, Sorg C, Sunderkotter C, Roth J (2007) Glucocorticoids induce differentiation of a specifically activated, anti-inflammatory subtype of human monocytes. Blood 109:1265–1274. doi:10.1182/blood-2006-02-001115 PubMedGoogle Scholar
  64. Escribano I, Rodriguez JC, Llorca B, Garcia-Pachon E, Ruiz M, Royo G (2007) Importance of the efflux pump systems in the resistance of Mycobacterium tuberculosis to fluoroquinolones and linezolid. Chemotherapy 53:397–401. doi:10.1159/000109769 PubMedGoogle Scholar
  65. Falkinham JO 3rd (2010) Hospital water filters as a source of Mycobacterium avium complex. J Med Microbiol 59:1198–1202. doi:10.1099/jmm.0.022376-0 PubMedGoogle Scholar
  66. Falkinham JO 3rd, Norton CD, LeChevallier MW (2001) Factors influencing numbers of Mycobacterium avium, Mycobacterium intracellulare, and other Mycobacteria in drinking water distribution systems. Appl Environ Microbiol 67:1225–1231PubMedGoogle Scholar
  67. Farhana A, Kumar S, Rathore SS, Ghosh PC, Ehtesham NZ, Tyagi AK, Hasnain SE (2008) Mechanistic insights into a novel exporter-importer system of Mycobacterium tuberculosis unravel its role in trafficking of iron. PLoS One 3:e2087. doi:10.1371/journal.pone.0002087 PubMedGoogle Scholar
  68. Ferhat M, Atlan D, Vianney A, Lazzaroni JC, Doublet P, Gilbert C (2009) The TolC protein of Legionella pneumophila plays a major role in multi-drug resistance and the early steps of host invasion. PLoS One 4:e7732. doi:10.1371/journal.pone.0007732 PubMedGoogle Scholar
  69. Frisk A, Schurr JR, Wang G, Bertucci DC, Marrero L, Hwang SH, Hassett DJ, Schurr MJ (2004) Transcriptome analysis of Pseudomonas aeruginosa after interaction with human airway epithelial cells. Infect Immun 72:5433–5438. doi:10.1128/IAI.72.9.5433-5438.2004 PubMedGoogle Scholar
  70. Garvey MI, Piddock LJ (2008) The efflux pump inhibitor reserpine selects multidrug-resistant Streptococcus pneumoniae strains that overexpress the ABC transporters PatA and PatB. Antimicrob Agents Chemother 52:1677–1685. doi:10.1128/AAC.01644-07 PubMedGoogle Scholar
  71. George KM, Chatterjee D, Gunawardana G, Welty D, Hayman J, Lee R, Small PL (1999) Mycolactone: a polyketide toxin from Mycobacterium ulcerans required for virulence. Science 283:854–857PubMedGoogle Scholar
  72. Grosset J (2003) Mycobacterium tuberculosis in the extracellular compartment: an underestimated adversary. Antimicrob Agents Chemother 47:833–836PubMedGoogle Scholar
  73. World Health Organization (2011) Guidelines for the programmatic management of drug-resistant tuberculosis, 2011 updateGoogle Scholar
  74. Gupta AK, Chauhan DS, Srivastava K, Das R, Batra S, Mittal M, Goswami P, Singhal N, Sharma VD, Venkatesan K, Hasnain SE, Katoch VM (2006) Estimation of efflux mediated multi-drug resistance and its correlation with expression levels of two major efflux pumps in mycobacteria. J Commun Dis 38:246–254PubMedGoogle Scholar
  75. Gupta AK, Katoch VM, Chauhan DS, Sharma R, Singh M, Venkatesan K, Sharma VD (2010) Microarray analysis of efflux pump genes in multidrug-resistant Mycobacterium tuberculosis during stress induced by common anti-tuberculous drugs. Microbial Drug Resist 16:21–28. doi:10.1089/mdr.2009.0054 Google Scholar
  76. Hagman KE, Pan W, Spratt BG, Balthazar JT, Judd RC, Shafer WM (1995) Resistance of Neisseria gonorrhoeae to antimicrobial hydrophobic agents is modulated by the mtrRCDE efflux system. Microbiology 141(Pt 3):611–622PubMedGoogle Scholar
  77. Hao P, Shi-Liang Z, Ju L, Ya-Xin D, Biao H, Xu W, Min-Tao H, Shou-Gang K, Ke W (2011) The role of ABC efflux pump, Rv1456c-Rv1457c-Rv1458c, from Mycobacterium tuberculosis clinical isolates in China. Folia Microbiol 56:549–553. doi:10.1007/s12223-011-0080-7 Google Scholar
  78. Helling RB, Janes BK, Kimball H, Tran T, Bundesmann M, Check P, Phelan D, Miller C (2002) Toxic waste disposal in Escherichia coli. J Bacteriol 184:3699–3703PubMedGoogle Scholar
  79. Ho RH, Kim RB (2005) Transporters and drug therapy: implications for drug disposition and disease. Clin Pharmacol Ther 78:260–277. doi:10.1016/j.clpt.2005.05.011 PubMedGoogle Scholar
  80. Hobby GL, Meyer K, Chaffee E (1942) Observations on the mechanism of action of penicillin. Proc Soc Exp Biol Med 50:281–288Google Scholar
  81. Jerse AE, Sharma ND, Simms AN, Crow ET, Snyder LA, Shafer WM (2003) A gonococcal efflux pump system enhances bacterial survival in a female mouse model of genital tract infection. Infect Immun 71:5576–5582PubMedGoogle Scholar
  82. Jiang X, Zhang W, Zhang Y, Gao F, Lu C, Zhang X, Wang H (2008) Assessment of efflux pump gene expression in a clinical isolate Mycobacterium tuberculosis by real-time reverse transcription PCR. Microbial Drug Resist 14:7–11. doi:10.1089/mdr.2008.0772 Google Scholar
  83. Jindani A, Aber VR, Edwards EA, Mitchison DA (1980) The early bactericidal activity of drugs in patients with pulmonary tuberculosis. Am Rev Respir Dis 121:939–949PubMedGoogle Scholar
  84. Johnson JL, Hadad DJ, Dietze R, Maciel EL, Sewali B, Gitta P, Okwera A, Mugerwa RD, Alcaneses MR, Quelapio MI, Tupasi TE, Horter L, Debanne SM, Eisenach KD, Boom WH (2009) Shortening treatment in adults with noncavitary tuberculosis and 2-month culture conversion. Am J Respir Crit Care Med 180:558–563. doi:10.1164/rccm.200904-0536OC PubMedGoogle Scholar
  85. Join-Lambert OF, Michea-Hamzehpour M, Kohler T, Chau F, Faurisson F, Dautrey S, Vissuzaine C, Carbon C, Pechere J (2001) Differential selection of multidrug efflux mutants by trovafloxacin and ciprofloxacin in an experimental model of Pseudomonas aeruginosa acute pneumonia in rats. Antimicrob Agents Chemother 45:571–576. doi:10.1128/AAC.45.2.571-576.2001 PubMedGoogle Scholar
  86. Kaatz GW (2005) Bacterial efflux pump inhibition. Curr Opin Invest Drugs 6:191–198Google Scholar
  87. Kalia NP, Mahajan P, Mehra R, Nargotra A, Sharma JP, Koul S, Khan IA (2012) Capsaicin, a novel inhibitor of the NorA efflux pump, reduces the intracellular invasion of Staphylococcus aureus. J Antimicrob Chemother. doi:10.1093/jac/dks232 PubMedGoogle Scholar
  88. Klyachko KA, Schuldiner S, Neyfakh AA (1997) Mutations affecting substrate specificity of the Bacillus subtilis multidrug transporter Bmr. J Bacteriol 179:2189–2193PubMedGoogle Scholar
  89. Kohler T, van Delden C, Curty LK, Hamzehpour MM, Pechere JC (2001) Overexpression of the MexEF-OprN multidrug efflux system affects cell-to-cell signaling in Pseudomonas aeruginosa. J Bacteriol 183:5213–5222PubMedGoogle Scholar
  90. Kraus D, Peschel A (2006) Molecular mechanisms of bacterial resistance to antimicrobial peptides. Curr Top Microbiol Immunol 306:231–250PubMedGoogle Scholar
  91. Kumar D, Rao KV (2011) Regulation between survival, persistence, and elimination of intracellular mycobacteria: a nested equilibrium of delicate balances. Microb Infect/Inst Pasteur 13:121–133. doi:10.1016/j.micinf.2010.10.009 Google Scholar
  92. Kupferwasser LI, Skurray RA, Brown MH, Firth N, Yeaman MR, Bayer AS (1999) Plasmid-mediated resistance to thrombin-induced platelet microbicidal protein in staphylococci: role of the qacA locus. Antimicrob Agents Chemother 43:2395–2399PubMedGoogle Scholar
  93. Lamarche MG, Deziel E (2011) MexEF-OprN efflux pump exports the Pseudomonas quinolone signal (PQS) precursor HHQ (4-hydroxy-2-heptylquinoline). PLoS One 6:e24310. doi:10.1371/journal.pone.0024310 PubMedGoogle Scholar
  94. Lamichhane G, Tyagi S, Bishai WR (2005) Designer arrays for defined mutant analysis to detect genes essential for survival of Mycobacterium tuberculosis in mouse lungs. Infect Immun 73:2533–2540. doi:10.1128/IAI.73.4.2533-2540.2005 PubMedGoogle Scholar
  95. Lamrabet O, Mba Medie F, Drancourt M (2012) Acanthamoeba polyphaga-enhanced growth of Mycobacterium smegmatis. PLoS One 7:e29833. doi:10.1371/journal.pone.0029833 PubMedGoogle Scholar
  96. Larsson C, Luna B, Ammerman NC, Maiga M, Agarwal N, Bishai WR (2012) Gene expression of Mycobacterium tuberculosis putative transcription factors whiB1-7 in redox environments. PLoS One 7:e37516. doi:10.1371/journal.pone.0037516 PubMedGoogle Scholar
  97. Lee A, Mao W, Warren MS, Mistry A, Hoshino K, Okumura R, Ishida H, Lomovskaya O (2000) Interplay between efflux pumps may provide either additive or multiplicative effects on drug resistance. J Bacteriol 182:3142–3150PubMedGoogle Scholar
  98. Leitner I, Nemeth J, Feurstein T, Abrahim A, Matzneller P, Lagler H, Erker T, Langer O, Zeitlinger M (2011) The third-generation P-glycoprotein inhibitor tariquidar may overcome bacterial multidrug resistance by increasing intracellular drug concentration. J Antimicrob Chemother 66:834–839. doi:10.1093/jac/dkq526 PubMedGoogle Scholar
  99. Lewis K (2010) Persister cells. Annu Rev Microbiol 64:357–372. doi:10.1146/annurev.micro.112408.134306 PubMedGoogle Scholar
  100. Li XZ, Nikaido H (2009) Efflux-mediated drug resistance in bacteria: an update. Drugs 69:1555–1623. doi:10.2165/11317030-000000000-00000 PubMedGoogle Scholar
  101. Li XZ, Nikaido H, Poole K (1995) Role of mexA-mexB-oprM in antibiotic efflux in Pseudomonas aeruginosa. Antimicrob Agents Chemother 39:1948–1953PubMedGoogle Scholar
  102. Lin J, Martinez A (2006) Effect of efflux pump inhibitors on bile resistance and in vivo colonization of Campylobacter jejuni. J Antimicrob Chemother 58:966–972. doi:10.1093/jac/dkl374 PubMedGoogle Scholar
  103. Lin J, Sahin O, Michel LO, Zhang Q (2003) Critical role of multidrug efflux pump CmeABC in bile resistance and in vivo colonization of Campylobacter jejuni. Infect Immun 71:4250–4259PubMedGoogle Scholar
  104. Linares JF, Lopez JA, Camafeita E, Albar JP, Rojo F, Martinez JL (2005) Overexpression of the multidrug efflux pumps MexCD-OprJ and MexEF-OprN is associated with a reduction of type III secretion in Pseudomonas aeruginosa. J Bacteriol 187:1384–1391. doi:10.1128/JB.187.4.1384-1391.2005 PubMedGoogle Scholar
  105. Linell F, Norden A (1954) Mycobacterium balnei, a new acid fast bacillus occurring in swimming pools and capable of producing skin lesions in humans. Acta Tuberc Scand Suppl 33:1–84PubMedGoogle Scholar
  106. Liu J, Takiff HE, Nikaido H (1996) Active efflux of fluoroquinolones in Mycobacterium smegmatis mediated by LfrA, a multidrug efflux pump. J Bacteriol 178:3791–3795PubMedGoogle Scholar
  107. Liu PT, Stenger S, Li H, Wenzel L, Tan BH, Krutzik SR, Ochoa MT, Schauber J, Wu K, Meinken C, Kamen DL, Wagner M, Bals R, Steinmeyer A, Zugel U, Gallo RL, Eisenberg D, Hewison M, Hollis BW, Adams JS, Bloom BR, Modlin RL (2006) Toll-like receptor triggering of a vitamin D-mediated human antimicrobial response. Science 311:1770–1773. doi:10.1126/science.1123933 PubMedGoogle Scholar
  108. Liu PT, Stenger S, Tang DH, Modlin RL (2007) Cutting edge: vitamin D-mediated human antimicrobial activity against Mycobacterium tuberculosis is dependent on the induction of cathelicidin. J Immunol 179:2060–2063PubMedGoogle Scholar
  109. Long Q, Zhou Q, Ji L, Wu J, Wang W, Xie J (2012) Mycobacterium smegmatis genomic characteristics associated with its saprophyte lifestyle. J Cell Biochem. doi:10.1002/jcb.24199 Google Scholar
  110. Louw GE, Warren RM, Gey van Pittius NC, Leon R, Jimenez A, Hernandez-Pando R, McEvoy CR, Grobbelaar M, Murray M, van Helden PD, Victor TC (2011) Rifampicin reduces susceptibility to ofloxacin in rifampicin-resistant Mycobacterium tuberculosis through efflux. Am J Respir Crit Care Med 184:269–276. doi:10.1164/rccm.201011-1924OC PubMedGoogle Scholar
  111. Louw GE, Warren RM, Gey van Pittius NC, McEvoy CR, Van Helden PD, Victor TC (2009) A balancing act: efflux/influx in mycobacterial drug resistance. Antimicrob Agents Chemother 53:3181–3189. doi:10.1128/AAC.01577-08 PubMedGoogle Scholar
  112. Ma D, Cook DN, Alberti M, Pon NG, Nikaido H, Hearst JE (1995) Genes acrA and acrB encode a stress-induced efflux system of Escherichia coli. Mol Microbiol 16:45–55PubMedGoogle Scholar
  113. Machado D, Couto I, Perdigao J, Rodrigues L, Portugal I, Baptista P, Veigas B, Amaral L, Viveiros M (2012) Contribution of efflux to the emergence of isoniazid and multidrug resistance in Mycobacterium tuberculosis. PLoS One 7:e34538. doi:10.1371/journal.pone.0034538 PubMedGoogle Scholar
  114. Mandell GL, Bennett JE, Dolin R (2010) Mandell, Douglas, and Bennett’s principles and practice of infectious diseases, 7th edn. Churchill Livingstone/Elsevier, PhiladelphiaGoogle Scholar
  115. Marquez B (2005) Bacterial efflux systems and efflux pumps inhibitors. Biochimie 87:1137–1147. doi:10.1016/j.biochi.2005.04.012 PubMedGoogle Scholar
  116. Martinez A, Lin J (2006) Effect of an efflux pump inhibitor on the function of the multidrug efflux pump CmeABC and antimicrobial resistance in campylobacter. Foodborne Pathog Dis 3:393–402. doi:10.1089/fpd.2006.3.393 PubMedGoogle Scholar
  117. Martins M, Viveiros M, Amaral L (2008) Inhibitors of Ca2 + and K + transport enhance intracellular killing of M. tuberculosis by non-killing macrophages. In vivo 22:69–75PubMedGoogle Scholar
  118. 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 104:737–762PubMedGoogle Scholar
  119. McMurry L, Petrucci RE Jr, Levy SB (1980) Active efflux of tetracycline encoded by four genetically different tetracycline resistance determinants in Escherichia coli. Proc Natl Acad Sci U S A 77:3974–3977PubMedGoogle Scholar
  120. Medjahed H, Gaillard JL, Reyrat JM (2010) Mycobacterium abscessus: a new player in the mycobacterial field. Trends Microbiol 18:117–123. doi:10.1016/j.tim.2009.12.007 PubMedGoogle Scholar
  121. Mitchison D, Davies G (2012) The chemotherapy of tuberculosis: past, present and future. Int J Tuberc Lung Dis: Off J Int Union Against Tuberc Lung Dis 16:724–732. doi:10.5588/ijtld.12.0083 Google Scholar
  122. Molle V, Soulat D, Jault JM, Grangeasse C, Cozzone AJ, Prost JF (2004) Two FHA domains on an ABC transporter, Rv1747, mediate its phosphorylation by PknF, a Ser/Thr protein kinase from Mycobacterium tuberculosis. FEMS Microbiol Lett 234:215–223. doi:10.1016/j.femsle.2004.03.033 PubMedGoogle Scholar
  123. Morris RP, Nguyen L, Gatfield J (2005) Ancestral antibiotic resistance in Mycobacterium tuberculosis. Proc Natl Acad Sci USA 102(34):12200–12205Google Scholar
  124. Nessar R, Cambau E, Reyrat JM, Murray A, Gicquel B (2012) Mycobacterium abscessus: a new antibiotic nightmare. J Antimicrob Chemother 67:810–818. doi:10.1093/jac/dkr578 PubMedGoogle Scholar
  125. Neyfakh AA (2002) Mystery of multidrug transporters: the answer can be simple. Mol Microbiol 44:1123–1130PubMedGoogle Scholar
  126. Nishino K, Latifi T, Groisman EA (2006) Virulence and drug resistance roles of multidrug efflux systems of Salmonella enterica serovar typhimurium. Mol Microbiol 59:126–141. doi:10.1111/j.1365-2958.2005.04940.x PubMedGoogle Scholar
  127. Ordonez E, Letek M, Valbuena N, Gil JA, Mateos LM (2005) Analysis of genes involved in arsenic resistance in Corynebacterium glutamicum ATCC 13032. Appl Environ Microbiol 71:6206–6215. doi:10.1128/AEM.71.10.6206-6215.2005 PubMedGoogle Scholar
  128. Padilla E, Llobet E, Domenech-Sanchez A, Martinez–Martinez L, Bengoechea JA, Alberti S (2010) Klebsiella pneumoniae AcrAB efflux pump contributes to antimicrobial resistance and virulence. Antimicrob Agents Chemother 54:177–183. doi:10.1128/AAC.00715-09 PubMedGoogle Scholar
  129. Pages JM, Amaral L (2009) Mechanisms of drug efflux and strategies to combat them: challenging the efflux pump of Gram-negative bacteria. Biochim Biophys Acta 1794:826–833. doi:10.1016/j.bbapap.2008.12.011 PubMedGoogle Scholar
  130. Parker D, Prince A (2011) Innate immunity in the respiratory epithelium. Am J Respir Cell Mol Biol 45:189–201. doi:10.1165/rcmb.2011-0011RT PubMedGoogle Scholar
  131. Pasca MR, Guglierame P, Arcesi F, Bellinzoni M, De Rossi E, Riccardi G (2004) Rv2686c-Rv2687c-Rv2688c, an ABC fluoroquinolone efflux pump in Mycobacterium Tuberculosis. Antimicrob Agents Chemother 48:3175–3178. doi:10.1128/AAC.48.8.3175-3178.2004 PubMedGoogle Scholar
  132. Pasca MR, Guglierame P, De Rossi E, Zara F, Riccardi G (2005) mmpL7 gene of Mycobacterium tuberculosis is responsible for isoniazid efflux in Mycobacterium smegmatis. Antimicrob Agents Chemother 49:4775–4777. doi:10.1128/AAC.49.11.4775-4777.2005 PubMedGoogle Scholar
  133. Perez A, Poza M, Fernandez A, Fernandez Mdel C, Mallo S, Merino M, Rumbo-Feal S, Cabral MP, Bou G (2012) Involvement of the AcrAB-TolC efflux pump in the resistance, fitness, and virulence of Enterobacter cloacae. Antimicrob Agents Chemother 56:2084–2090. doi:10.1128/AAC.05509-11 PubMedGoogle Scholar
  134. Piddock LJ (2006a) Clinically relevant chromosomally encoded multidrug resistance efflux pumps in bacteria. Clin Microbiol Rev 19:382–402. doi:10.1128/CMR.19.2.382-402.2006 PubMedGoogle Scholar
  135. Piddock LJ (2006b) Multidrug-resistance efflux pumps—not just for resistance. Nat Rev Microbiol 4:629–636. doi:10.1038/nrmicro1464 PubMedGoogle Scholar
  136. Pierre-Audigier C, Jouanguy E, Lamhamedi S, Altare F, Rauzier J, Vincent V, Canioni D, Emile JF, Fischer A, Blanche S, Gaillard JL, Casanova JL (1997) Fatal disseminated Mycobacterium smegmatis infection in a child with inherited interferon gamma receptor deficiency. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America 24:982–984Google Scholar
  137. Platz GJ, Bublitz DC, Mena P, Benach JL, Furie MB, Thanassi DG (2010) A tolC mutant of Francisella tularensis is hypercytotoxic compared to the wild type and elicits increased proinflammatory responses from host cells. Infect Immun 78:1022–1031. doi:10.1128/IAI.00992-09 PubMedGoogle Scholar
  138. Posadas DM, Martin FA, Sabio y Garcia JV, Spera JM, Delpino MV, Baldi P, Campos E, Cravero SL, Zorreguieta A (2007) The TolC homologue of Brucella suis is involved in resistance to antimicrobial compounds and virulence. Infect Immun 75:379–389. doi:10.1128/IAI.01349-06 PubMedGoogle Scholar
  139. Quillin SJ, Schwartz KT, Leber JH (2011) The novel Listeria monocytogenes bile sensor BrtA controls expression of the cholic acid efflux pump MdrT. Mol Microbiol 81:129–142. doi:10.1111/j.1365-2958.2011.07683.x PubMedGoogle Scholar
  140. Ramakrishnan L, Federspiel NA, Falkow S (2000) Granuloma-specific expression of Mycobacterium virulence proteins from the glycine-rich PE-PGRS family. Science 288:1436–1439PubMedGoogle Scholar
  141. Ramon-Garcia S, Martin C, Thompson CJ, Ainsa JA (2009) Role of the Mycobacterium tuberculosis P55 efflux pump in intrinsic drug resistance, oxidative stress responses, and growth. Antimicrob Agents Chemother 53:3675–3682. doi:10.1128/AAC.00550-09 PubMedGoogle Scholar
  142. Reddy TB, Riley R, Wymore F, Montgomery P, DeCaprio D, Engels R, Gellesch M, Hubble J, Jen D, Jin H, Koehrsen M, Larson L, Mao M, Nitzberg M, Sisk P, Stolte C, Weiner B, White J, Zachariah ZK, Sherlock G, Galagan JE, Ball CA, Schoolnik GK (2009) TB database: an integrated platform for tuberculosis research. Nucleic Acids Res 37:D499–D508. doi:10.1093/nar/gkn652 PubMedGoogle Scholar
  143. Rengarajan J, Bloom BR, Rubin EJ (2005) Genome-wide requirements for Mycobacterium tuberculosis adaptation and survival in macrophages. Proc Natl Acad Sci USA 102:8327–8332. doi:10.1073/pnas.0503272102 PubMedGoogle Scholar
  144. Richter E, Rusch-Gerdes S, Hillemann D (2007) First linezolid-resistant clinical isolates of Mycobacterium tuberculosis. Antimicrob Agents Chemother 51:1534–1536. doi:10.1128/AAC.01113-06 PubMedGoogle Scholar
  145. Ripoll F, Pasek S, Schenowitz C, Dossat C, Barbe V, Rottman M, Macheras E, Heym B, Herrmann JL, Daffe M, Brosch R, Risler JL, Gaillard JL (2009) Non mycobacterial virulence genes in the genome of the emerging pathogen Mycobacterium abscessus. PLoS ONE 4:e5660. doi:10.1371/journal.pone.0005660 PubMedGoogle Scholar
  146. Rodrigues L, Ainsa JA, Amaral L, Viveiros M (2011a) Inhibition of drug efflux in mycobacteria with phenothiazines and other putative efflux inhibitors. Recent Pat Anti-Infect Drug Discovery 6:118–127Google Scholar
  147. Rodrigues L, Machado D, Couto I, Amaral L, Viveiros M (2011b) Contribution of efflux activity to isoniazid resistance in the Mycobacterium tuberculosis complex. Infection, genetics and evolution : journal of molecular epidemiology and evolutionary genetics in infectious diseases. doi:10.1016/j.meegid.2011.08.009 PubMedGoogle Scholar
  148. Rodrigues L, Machado D, Couto I, Amaral L, Viveiros M (2012) Contribution of efflux activity to isoniazid resistance in the Mycobacterium tuberculosis complex. Infection, genetics and evolution : journal of molecular epidemiology and evolutionary genetics in infectious diseases 12:695–700. doi:10.1016/j.meegid.2011.08.009 PubMedGoogle Scholar
  149. Rodrigues LC, Lockwood D (2011) Leprosy now: epidemiology, progress, challenges, and research gaps. Lancet Infect Dis 11:464–470. doi:10.1016/S1473-3099(11)70006-8 PubMedGoogle Scholar
  150. Rohde KH, Veiga DF, Caldwell S, Balazsi G, Russell DG (2012) Linking the transcriptional profiles and the physiological states of Mycobacterium tuberculosis during an extended intracellular infection. PLoS Pathog 8:e1002769. doi:10.1371/journal.ppat.1002769 PubMedGoogle Scholar
  151. Rosenberg EY, Bertenthal D, Nilles ML, Bertrand KP, Nikaido H (2003) Bile salts and fatty acids induce the expression of Escherichia coli AcrAB multidrug efflux pump through their interaction with rob regulatory protein. Mol Microbiol 48:1609–1619PubMedGoogle Scholar
  152. Saier MH Jr, Yen MR, Noto K, Tamang DG, Elkan C (2009) The transporter classification database: recent advances. Nucleic Acids Res 37:D274–D278. doi:10.1093/nar/gkn862 PubMedGoogle Scholar
  153. Sassetti CM, Rubin EJ (2003) Genetic requirements for mycobacterial survival during infection. Proc Natl Acad Sci USA 100:12989–12994. doi:10.1073/pnas.2134250100 PubMedGoogle Scholar
  154. Schaefer WB (1954) The effect of isoniazid on growing and resting tubercle bacilli. Am Rev Tuberc 69:125–127PubMedGoogle Scholar
  155. Schnappinger D, Ehrt S, Voskuil MI, Liu Y, Mangan JA, Monahan IM, Dolganov G, Efron B, Butcher PD, Nathan C, Schoolnik GK (2003) Transcriptional adaptation of Mycobacterium tuberculosis within macrophages: insights into the phagosomal environment. J Exp Med 198:693–704. doi:10.1084/jem.20030846 jem.20030846 [pii]PubMedGoogle Scholar
  156. Shafer WM, Balthazar JT, Hagman KE, Morse SA (1995) Missense mutations that alter the DNA-binding domain of the MtrR protein occur frequently in rectal isolates of Neisseria gonorrhoeae that are resistant to faecal lipids. Microbiology 141(Pt 4):907–911PubMedGoogle Scholar
  157. Shafer WM, Qu X, Waring AJ, Lehrer RI (1998) Modulation of Neisseria gonorrhoeae susceptibility to vertebrate antibacterial peptides due to a member of the resistance/nodulation/division efflux pump family. Proc Natl Acad Sci USA 95:1829–1833PubMedGoogle Scholar
  158. Sharma S, Kumar M, Nargotra A, Koul S, Khan IA (2010) Piperine as an inhibitor of Rv1258c, a putative multidrug efflux pump of Mycobacterium tuberculosis. J Antimicrob Chemother 65:1694–1701. doi:10.1093/jac/dkq186 PubMedGoogle Scholar
  159. Shepard CC (1957) Growth characteristics of tubercle bacilli and certain other mycobacteria in HeLa cells. J Exp Med 105:39–48PubMedGoogle Scholar
  160. Siddiqi N, Das R, Pathak N, Banerjee S, Ahmed N, Katoch VM, Hasnain SE (2004) Mycobacterium tuberculosis isolate with a distinct genomic identity overexpresses a tap-like efflux pump. Infection 32:109–111. doi:10.1007/s15010-004-3097-x PubMedGoogle Scholar
  161. Simeone R, Bobard A, Lippmann J, Bitter W, Majlessi L, Brosch R, Enninga J (2012) Phagosomal rupture by Mycobacterium tuberculosis results in toxicity and host cell death. PLoS Pathog 8:e1002507. doi:10.1371/journal.ppat.1002507 PubMedGoogle Scholar
  162. Singh M, Jadaun GP, Ramdas, Srivastava K, Chauhan V, Mishra R, Gupta K, Nair S, Chauhan DS, Sharma VD, Venkatesan K, Katoch VM (2011) Effect of efflux pump inhibitors on drug susceptibility of ofloxacin resistant Mycobacterium tuberculosis isolates. Indian J Med Res 133:535–540PubMedGoogle Scholar
  163. Singh P, Cole ST (2011) Mycobacterium leprae: genes, pseudogenes and genetic diversity. Future Microbiol 6:57–71. doi:10.2217/fmb.10.153 PubMedGoogle Scholar
  164. Spies FS, da Silva PE, Ribeiro MO, Rossetti ML, Zaha A (2008) Identification of mutations related to streptomycin resistance in clinical isolates of Mycobacterium tuberculosis and possible involvement of efflux mechanism. Antimicrob Agents Chemother 52:2947–2949. doi:10.1128/AAC.01570-07 PubMedGoogle Scholar
  165. Spivey VL, Molle V, Whalan RH, Rodgers A, Leiba J, Stach L, Walker KB, Smerdon SJ, Buxton RS (2011) Forkhead-associated (FHA) domain containing ABC transporter Rv1747 is positively regulated by Ser/Thr phosphorylation in Mycobacterium tuberculosis. J Biol Chem 286:26198–26209. doi:10.1074/jbc.M111.246132 PubMedGoogle Scholar
  166. Srinivasan K (2007) Black pepper and its pungent principle-piperine: a review of diverse physiological effects. Crit Rev Food Sci Nutr 47:735–748. doi:10.1080/10408390601062054 PubMedGoogle Scholar
  167. Srivastava S, Musuka S, Sherman C, Meek C, Leff R, Gumbo T (2010) Efflux-pump-derived multiple drug resistance to ethambutol monotherapy in Mycobacterium tuberculosis and the pharmacokinetics and pharmacodynamics of ethambutol. J Infect Dis 201:1225–1231. doi:10.1086/651377 PubMedGoogle Scholar
  168. Stamm LM, Morisaki JH, Gao LY, Jeng RL, McDonald KL, Roth R, Takeshita S, Heuser J, Welch MD, Brown EJ (2003) Mycobacterium marinum escapes from phagosomes and is propelled by actin-based motility. J Exp Med 198:1361–1368. doi:10.1084/jem.20031072 PubMedGoogle Scholar
  169. Stinear TP, Seemann T, Harrison PF, Jenkin GA, Davies JK, Johnson PD, Abdellah Z, Arrowsmith C, Chillingworth T, Churcher C, Clarke K, Cronin A, Davis P, Goodhead I, Holroyd N, Jagels K, Lord A, Moule S, Mungall K, Norbertczak H, Quail MA, Rabbinowitsch E, Walker D, White B, Whitehead S, Small PL, Brosch R, Ramakrishnan L, Fischbach MA, Parkhill J, Cole ST (2008) Insights from the complete genome sequence of Mycobacterium marinum on the evolution of Mycobacterium tuberculosis. Genome Res 18:729–741. doi:10.1101/gr.075069.107 PubMedGoogle Scholar
  170. Stone BJ, Miller VL (1995) Salmonella enteritidis has a homologue of tolC that is required for virulence in BALB/c mice. Mol Microbiol 17:701–712PubMedGoogle Scholar
  171. Taylor DL, Bina XR, Bina JE (2012) Vibrio cholerae VexH encodes a multiple drug efflux pump that contributes to the production of cholera toxin and the toxin co-regulated pilus. PLoS One 7:e38208. doi:10.1371/journal.pone.0038208 PubMedGoogle Scholar
  172. Tekaia F, Gordon SV, Garnier T, Brosch R, Barrell BG, Cole ST (1999) Analysis of the proteome of Mycobacterium tuberculosis in silico. Tuber Lung Dis 79:329–342PubMedGoogle Scholar
  173. Thanassi DG, Cheng LW, Nikaido H (1997) Active efflux of bile salts by Escherichia coli. J Bacteriol 179:2512–2518PubMedGoogle Scholar
  174. Tsukamura M (1976) Properties of Mycobacterium smegmatis freshly isolated from soil. Japan J Microbiol 20:355–356Google Scholar
  175. Tzeng YL, Ambrose KD, Zughaier S, Zhou X, Miller YK, Shafer WM, Stephens DS (2005) Cationic antimicrobial peptide resistance in Neisseria meningitidis. J Bacteriol 187:5387–5396. doi:10.1128/JB.187.15.5387-5396.2005 PubMedGoogle Scholar
  176. van der Wel N, Hava D, Houben D, Fluitsma D, van Zon M, Pierson J, Brenner M, Peters PJ (2007) M. tuberculosis and M. leprae translocate from the phagolysosome to the cytosol in myeloid cells. Cell 129:1287–1298. doi:10.1016/j.cell.2007.05.059 PubMedGoogle Scholar
  177. Viveiros M, Portugal I, Bettencourt R, Victor TC, Jordaan AM, Leandro C, Ordway D, Amaral L (2002) Isoniazid-induced transient high-level resistance in Mycobacterium tuberculosis. Antimicrob Agents Chemother 46:2804–2810PubMedGoogle Scholar
  178. Wallace RJ Jr, Nash DR, Tsukamura M, Blacklock ZM, Silcox VA (1988) Human disease due to Mycobacterium smegmatis. J Infect Dis 158:52–59PubMedGoogle Scholar
  179. Wallis RS, Patil S, Cheon SH, Edmonds K, Phillips M, Perkins MD, Joloba M, Namale A, Johnson JL, Teixeira L, Dietze R, Siddiqi S, Mugerwa RD, Eisenach K, Ellner JJ (1999) Drug tolerance in Mycobacterium tuberculosis. Antimicrob Agents Chemother 43:2600–2606PubMedGoogle Scholar
  180. Wansbrough-Jones M, Phillips R (2006) Buruli ulcer: emerging from obscurity. Lancet 367:1849–1858. doi:10.1016/S0140-6736(06)68807-7 PubMedGoogle Scholar
  181. Ward SK, Abomoelak B, Hoye EA, Steinberg H, Talaat AM (2010) CtpV: a putative copper exporter required for full virulence of Mycobacterium tuberculosis. Mol Microbiol 77:1096–1110. doi:10.1111/j.1365-2958.2010.07273.x PubMedGoogle Scholar
  182. Warner DM, Levy SB (2010) Different effects of transcriptional regulators MarA, SoxS and Rob on susceptibility of Escherichia coli to cationic antimicrobial peptides (CAMPs): Rob-dependent CAMP induction of the marRAB operon. Microbiology 156:570–578. doi:10.1099/mic.0.033415-0 PubMedGoogle Scholar
  183. Warner DM, Shafer WM, Jerse AE (2008) Clinically relevant mutations that cause derepression of the Neisseria gonorrhoeae MtrC-MtrD-MtrE efflux pump system confer different levels of antimicrobial resistance and in vivo fitness. Mol Microbiol 70:462–478. doi:10.1111/j.1365-2958.2008.06424.x PubMedGoogle Scholar
  184. Woodward JJ, Iavarone AT, Portnoy DA (2010) c-di-AMP secreted by intracellular Listeria monocytogenes activates a host type I interferon response. Science 328:1703–1705. doi:10.1126/science.1189801 PubMedGoogle Scholar
  185. Woolridge DP, Vazquez-Laslop N, Markham PN, Chevalier MS, Gerner EW, Neyfakh AA (1997) Efflux of the natural polyamine spermidine facilitated by the Bacillus subtilis multidrug transporter Blt. The Journal of biological chemistry 272:8864–8866PubMedGoogle Scholar
  186. Wu Y, Vulic M, Keren I, Lewis K (2012) Role of oxidative stress in persister tolerance. Antimicrob Agents Chemother. doi:10.1128/AAC.00921-12 Google Scholar
  187. Yamazaki Y, Danelishvili L, Wu M, Hidaka E, Katsuyama T, Stang B, Petrofsky M, Bildfell R, Bermudez LE (2006) The ability to form biofilm influences Mycobacterium avium invasion and translocation of bronchial epithelial cells. Cell Microbiol 8:806–814. doi:10.1111/j.1462-5822.2005.00667.x PubMedGoogle Scholar
  188. Yanong RP, Pouder DB, Falkinham JO 3rd (2010) Association of mycobacteria in recirculating aquaculture systems and mycobacterial disease in fish. J Aquat Anim Health 22:219–223. doi:10.1577/H10-009.1 PubMedGoogle Scholar
  189. Zahner D, Zhou X, Chancey ST, Pohl J, Shafer WM, Stephens DS (2010) Human antimicrobial peptide LL-37 induces MefE/Mel-mediated macrolide resistance in Streptococcus pneumoniae. Antimicrob Agents Chemother 54:3516–3519. doi:10.1128/AAC.01756-09 PubMedGoogle Scholar
  190. Zhang M, Yue J, Yang YP, Zhang HM, Lei JQ, Jin RL, Zhang XL, Wang HH (2005) Detection of mutations associated with isoniazid resistance in Mycobacterium tuberculosis isolates from China. J Clin Microbiol 43:5477–5482. doi:10.1128/JCM.43.11.5477-5482.2005 PubMedGoogle Scholar
  191. Zierski M, Bek E, Long MW, Snider DE Jr (1980) Short-course (6 month) cooperative tuberculosis study in Poland: results 18 months after completion of treatment. Am Rev Respir Dis 122:879–889PubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2012

Authors and Affiliations

  • John D. Szumowski
    • 1
  • Kristin N. Adams
    • 2
  • Paul H. Edelstein
    • 3
  • Lalita Ramakrishnan
    • 1
    • 2
    • 4
  1. 1.Department of Medicine (Division of Infectious Diseases)University of WashingtonSeattleUSA
  2. 2.Department of MicrobiologyUniversity of WashingtonSeattleUSA
  3. 3.Departments of Pathology, Laboratory Medicine, and Medicine (Division of Infectious Diseases)University of PennsylvaniaPhiladelphiaUSA
  4. 4.Department of ImmunologyUniversity of WashingtonSeattleUSA

Personalised recommendations