Advertisement

Phenotypic Tolerance and Bacterial Persistence

  • Carl Nathan
Chapter
Part of the Emerging Infectious Diseases of the 21st Century book series (EIDC)

Abstract

When a bacterial population that was susceptible to a given antibiotic gives rise to a member that is resistant to the antibiotic, the best-understood mechanisms are those that are heritable by that cell’s progeny. Less well understood is nonheritable antibiotic resistance—resistance that is neither permanent in a given bacterium nor passed to its progeny. Nonheritable resistance is also called phenotypic tolerance. This chapter distinguishes two classes of phenotypic tolerance—one that can potentially be overcome by using several antibiotics in combination and another that requires finding new antibiotics that can kill bacteria in non-replicating states. Such states are often imposed by conditions in the host that constrain the bacteria without eliminating them, including host immunity and antibiotics themselves.

Notes

Acknowledgments

I am grateful to K. Burns-Huang, B. Gold, K. Rhee, K. Saito, and T. Warrier (Weill Cornell Medicine) for critical comments. I am thankful for the support of the Tri-Institutional TB Research Unit (NIH U19 AI111143) and the Milstein Program in Chemical Biology and Translational Medicine. The Department of Microbiology and Immunology is supported by the William Randolph Hearst Charitable Trust.

References

  1. 1.
    Nathan C. Cooperative development of antimicrobials: looking back to look ahead. Nat Rev Microbiol. 2015;13(10):651–7.PubMedCrossRefGoogle Scholar
  2. 2.
    Payne DJ, Gwynn MN, Holmes DJ, Pompliano DL. Drugs for bad bugs: confronting the challenges of antibacterial discovery. Nat Rev Drug Discov. 2007;6(1):29–40.PubMedCrossRefPubMedCentralGoogle Scholar
  3. 3.
    Brown K. Penicillin man: Alexander Fleming and the antibiotic revolution. Stroud: History Press; UK. 2013.Google Scholar
  4. 4.
    O’Neill J. Tackling drug-resistant infections globally. Review on Antimicrobial Resistance. London, England, UK. 2014.Google Scholar
  5. 5.
    White House. National action plan for combating antibiotic-resistant bacteria. Washington, DC. 2015. 62 pp.Google Scholar
  6. 6.
    O’Neill J. Tackling drug resistant infections globally: final report and recommendations. Review on Antimicrobial Resistance. London, England, UK. 2016.Google Scholar
  7. 7.
    Outterson K, Rex JH, Jinks T, Jackson P, Hallinan J, Karp S, et al. Accelerating global innovation to address antibacterial resistance: introducing CARB-X. Nat Rev Drug Discov. 2016;15(9):589–90.PubMedCrossRefGoogle Scholar
  8. 8.
    Bagley N, Outterson K. How to avoid a post-antibiotic world. New York Times. 2017:Op-Ed.Google Scholar
  9. 9.
    United Nations. Draft political declaration of the high-level meeting of the General Assembly on antimicrobial resistance. New York City, New York. 2016.Google Scholar
  10. 10.
    Nathan C. Antibiotics at the crossroads. Nature. 2004;431(7011):899–902.PubMedCrossRefPubMedCentralGoogle Scholar
  11. 11.
    Nathan C. Fresh approaches to anti-infective therapies. Sci Transl Med. 2012;4(140):140sr2.PubMedPubMedCentralCrossRefGoogle Scholar
  12. 12.
    Nathan C, Cars O. Antibiotic resistance–problems, progress, and prospects. N Engl J Med. 2014;371(19):1761–3.PubMedCrossRefPubMedCentralGoogle Scholar
  13. 13.
    Nathan C. Making space for anti-infective drug discovery. Cell Host Microbe. 2011;9(5):343–8.PubMedCrossRefPubMedCentralGoogle Scholar
  14. 14.
    Nathan C. Taming tuberculosis: a challenge for science and society. Cell Host Microbe. 2009;5(3):220–4.PubMedCrossRefPubMedCentralGoogle Scholar
  15. 15.
    Pietersen E, Ignatius E, Streicher EM, Mastrapa B, Padanilam X, Pooran A, et al. Long-term outcomes of patients with extensively drug-resistant tuberculosis in South Africa: a cohort study. Lancet. 2014;383(9924):1230–9.PubMedCrossRefPubMedCentralGoogle Scholar
  16. 16.
    Coscolla M, Copin R, Sutherland J, Gehre F, de Jong B, Owolabi O, et al. M. tuberculosis T cell epitope analysis reveals paucity of antigenic variation and identifies rare variable TB antigens. Cell Host Microbe. 2015;18(5):538–48.PubMedPubMedCentralCrossRefGoogle Scholar
  17. 17.
    Marakalala MJ, Raju RM, Sharma K, Zhang YJ, Eugenin EA, Prideaux B, et al. Inflammatory signaling in human tuberculosis granulomas is spatially organized. Nat Med. 2016;22(5):531–8.PubMedPubMedCentralCrossRefGoogle Scholar
  18. 18.
    Bhullar K, Waglechner N, Pawlowski A, Koteva K, Banks ED, Johnston MD, et al. Antibiotic resistance is prevalent in an isolated cave microbiome. PLoS One. 2012;7(4):e34953.PubMedPubMedCentralCrossRefGoogle Scholar
  19. 19.
    Kling A, Lukat P, Almeida DV, Bauer A, Fontaine E, Sordello S, et al. Antibiotics. Targeting DnaN for tuberculosis therapy using novel griselimycins. Science. 2015;348(6239):1106–12.PubMedCrossRefGoogle Scholar
  20. 20.
    de Carvalho LP, Lin G, Jiang X, Nathan C. Nitazoxanide kills replicating and nonreplicating Mycobacterium tuberculosis and evades resistance. J Med Chem. 2009;52(19):5789–92.PubMedCrossRefGoogle Scholar
  21. 21.
    Ling LL, Schneider T, Peoples AJ, Spoering AL, Engels I, Conlon BP, et al. A new antibiotic kills pathogens without detectable resistance. Nature. 2015;517(7535):455–9.PubMedCrossRefPubMedCentralGoogle Scholar
  22. 22.
    Moreira W, Aziz DB, Dick T. Boromycin kills mycobacterial persisters without detectable resistance. Front Microbiol. 2016;7:199.PubMedPubMedCentralGoogle Scholar
  23. 23.
    Van Boeckel TP, Brower C, Gilbert M, Grenfell BT, Levin SA, Robinson TP, et al. Global trends in antimicrobial use in food animals. Proc Natl Acad Sci U S A. 2015;112(18):5649–54.PubMedPubMedCentralCrossRefGoogle Scholar
  24. 24.
    Alsultan A, Peloquin CA. Therapeutic drug monitoring in the treatment of tuberculosis: an update. Drugs. 2014;74(8):839–54.PubMedCrossRefGoogle Scholar
  25. 25.
    Wilkins JJ, Savic RM, Karlsson MO, Langdon G, McIlleron H, Pillai G, et al. Population pharmacokinetics of rifampin in pulmonary tuberculosis patients, including a semimechanistic model to describe variable absorption. Antimicrob Agents Chemother. 2008;52(6):2138–48.PubMedPubMedCentralCrossRefGoogle Scholar
  26. 26.
    Um SW, Lee SW, Kwon SY, Yoon HI, Park KU, Song J, et al. Low serum concentrations of anti-tuberculosis drugs and determinants of their serum levels. Int J Tuberc Lung Dis. 2007;11(9):972–8.PubMedGoogle Scholar
  27. 27.
    Fleming-Dutra KE, Hersh AL, Shapiro DJ, Bartoces M, Enns EA, File TM Jr, et al. Prevalence of inappropriate antibiotic prescriptions among US Ambulatory Care Visits, 2010–2011. JAMA. 2016;315(17):1864–73.CrossRefGoogle Scholar
  28. 28.
    Warrier T, Kapilashrami K, Argyrou A, Ioerger TR, Little D, Murphy KC, et al. N-methylation of a bactericidal compound as a resistance mechanism in Mycobacterium tuberculosis. Proc Natl Acad Sci U S A. 2016;113(31):E4523–30.PubMedPubMedCentralCrossRefGoogle Scholar
  29. 29.
    El-Halfawy OM, Klett J, Ingram RJ, Loutet SA, Murphy ME, Martin-Santamaria S, et al. Antibiotic capture by bacterial Lipocalins uncovers an extracellular mechanism of intrinsic antibiotic resistance. MBio. 2017;8(2)Google Scholar
  30. 30.
    Gold B, Nathan C. Targeting phenotypically tolerant Mycobacterium tuberculosis. In: Jacobs Jr WR, McShane H, Mizrahi V, Orme I, editors. Tuberculosis and the tubercle Bacillus. 2nd ed: American Society of Microbiolgy Press; 2017.Google Scholar
  31. 31.
    Fox W, Sutherland IA. Five-year assessment of patients in a controlled trial of streptomycin, Para-aminosalicylic acid, and streptomycin plus Para-aminosalicylic acid, in pulmonary tuberculosis. Q J Med. 1956;25(98):221–43.PubMedPubMedCentralGoogle Scholar
  32. 32.
    Lin CH, Chi CY, Shih HP, Ding JY, Lo CC, Wang SY, et al. Identification of a major epitope by anti-interferon-gamma autoantibodies in patients with mycobacterial disease. Nat Med. 2016;22(9):994–1001.PubMedCrossRefGoogle Scholar
  33. 33.
    Xie QW, Cho HJ, Calaycay J, Mumford RA, Swiderek KM, Lee TD, et al. Cloning and characterization of inducible nitric oxide synthase from mouse macrophages. Science. 1992;256(5054):225–8.PubMedCrossRefGoogle Scholar
  34. 34.
    McCune RM, Feldmann FM, Lambert HP, McDermott W. Microbial persistence. I. The capacity of tubercle bacilli to survive sterilization in mouse tissues. J Exp Med. 1966;123(3):445–68.PubMedPubMedCentralCrossRefGoogle Scholar
  35. 35.
    Gold B, Pingle M, Brickner SJ, Shah N, Roberts J, Rundell M, et al. Nonsteroidal anti-inflammatory drug sensitizes Mycobacterium tuberculosis to endogenous and exogenous antimicrobials. Proc Natl Acad Sci U S A. 2012;109(40):16004–11.PubMedPubMedCentralCrossRefGoogle Scholar
  36. 36.
    Helaine S, Cheverton AM, Watson KG, Faure LM, Matthews SA, Holden DW. Internalization of Salmonella by macrophages induces formation of nonreplicating persisters. Science. 2014;343(6167):204–8.PubMedCrossRefGoogle Scholar
  37. 37.
    Tuomanen E. Phenotypic tolerance: the search for beta-lactam antibiotics that kill nongrowing bacteria. Rev Infect Dis. 1986;8(Suppl 3):S279–91.PubMedCrossRefGoogle Scholar
  38. 38.
    Liu Y, Tan S, Huang L, Abramovitch RB, Rohde KH, Zimmerman MD, et al. Immune activation of the host cell induces drug tolerance in Mycobacterium tuberculosis both in vitro and in vivo. J Exp Med. 2016;213(5):809–25.PubMedPubMedCentralCrossRefGoogle Scholar
  39. 39.
    Zemke AC, Gladwin MT, Bomberger JM. Sodium nitrite blocks the activity of aminoglycosides against Pseudomonas aeruginosa biofilms. Antimicrob Agents Chemother. 2015;59(6):3329–34.PubMedPubMedCentralCrossRefGoogle Scholar
  40. 40.
    Gusarov I, Shatalin K, Starodubtseva M, Nudler E. Endogenous nitric oxide protects bacteria against a wide spectrum of antibiotics. Science. 2009;325(5946):1380–4.PubMedPubMedCentralCrossRefGoogle Scholar
  41. 41.
    Group ICGDCS. A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease. The International Chronic Granulomatous Disease Cooperative Study Group. N Engl J Med. 1991;324(8):509–16.CrossRefGoogle Scholar
  42. 42.
    Sun K, Yajjala VK, Bauer C, Talmon GA, Fischer KJ, Kielian T, et al. Nox2-derived oxidative stress results in inefficacy of antibiotics against post-influenza S. aureus pneumonia. J Exp Med. 2016;213(9):1851–64.PubMedPubMedCentralCrossRefGoogle Scholar
  43. 43.
    Nathan C, Gold B, Lin G, Stegman M, de Carvalho LP, Vandal O, et al. A philosophy of anti-infectives as a guide in the search for new drugs for tuberculosis. Tuberculosis (Edinb). 2008;88(Suppl 1):S25–33.CrossRefGoogle Scholar
  44. 44.
    Levin-Reisman I, Ronin I, Gefen O, Braniss I, Shoresh N, Balaban NQ. Antibiotic tolerance facilitates the evolution of resistance. Science. 2017;355(6327):826–30.PubMedCrossRefPubMedCentralGoogle Scholar
  45. 45.
    Abraham EP, Chain E. Purification of penicillin. Nature. 1942;149:328.CrossRefGoogle Scholar
  46. 46.
    Hobby GL, Meyer K, Chaffee E. Observations on the mechanism of action of penicillin. Proc Soc Exp Biol Med. 1942;50:281–5.CrossRefGoogle Scholar
  47. 47.
    Bigger J. Treatment of staphylococcal infections with penicillin by intermittent sterilisation. Lancet. 1944;244:497–500.CrossRefGoogle Scholar
  48. 48.
    Nathan C, Barry CE 3rd. TB drug development: immunology at the table. Immunol Rev. 2015;264(1):308–18.PubMedPubMedCentralCrossRefGoogle Scholar
  49. 49.
    Kohanski MA, DePristo MA, Collins JJ. Sublethal antibiotic treatment leads to multidrug resistance via radical-induced mutagenesis. Mol Cell. 2010;37(3):311–20.PubMedPubMedCentralCrossRefGoogle Scholar
  50. 50.
    Boshoff HI, Reed MB, Barry CE 3rd, Mizrahi V. DnaE2 polymerase contributes to in vivo survival and the emergence of drug resistance in Mycobacterium tuberculosis. Cell. 2003;113(2):183–93.PubMedCrossRefGoogle Scholar
  51. 51.
    Xu HS, Roberts N, Singleton FL, Attwell RW, Grimes DJ, Colwell RR. Survival and viability of nonculturable Escherichia coli and Vibrio cholerae in the estuarine and marine environment. Microb Ecol. 1982;8(4):313–23.PubMedCrossRefGoogle Scholar
  52. 52.
    Chengalroyen MD, Beukes GM, Gordhan BG, Streicher EM, Churchyard G, Hafner R, et al. Detection and quantification of differentially culturable Tubercle Bacteria in sputum from tuberculosis patients. Am J Respir Crit Care Med. 2016;194(12):1532–40.PubMedPubMedCentralCrossRefGoogle Scholar
  53. 53.
    Dartois V, Saito K, Warrier T, Nathan C. Editorial: new evidence for the complexity of the population structure of Mycobacterium tuberculosis increases the diagnostic and biologic challenges. Am J Resp Crit Care Med. 2016;194:1448–50.PubMedCrossRefGoogle Scholar
  54. 54.
    Mukamolova GV, Turapov O, Malkin J, Woltmann G, Barer MR. Resuscitation-promoting factors reveal an occult population of tubercle Bacilli in Sputum. Am J Respir Crit Care Med. 2010;181(2):174–80.PubMedCrossRefPubMedCentralGoogle Scholar
  55. 55.
    Saito K, Warrier T, Somersan-Karakaya S, Kaminski L, Mi J, Jiang X, et al. Rifamycin action on RNA polymerase in antibiotic-tolerant Mycobacterium tuberculosis results in differentially detectable populations. Proc Natl Acad Sci U S A. 2017;114:E4832–40.PubMedPubMedCentralCrossRefGoogle Scholar
  56. 56.
    Vilcheze C, Hartman T, Weinrick B, Jain P, Weisbrod TR, Leung LW, et al. Enhanced respiration prevents drug tolerance and drug resistance in Mycobacterium tuberculosis. Proc Natl Acad Sci U S A. 2017;114(17):4495–500.PubMedPubMedCentralCrossRefGoogle Scholar
  57. 57.
    Brauner A, Fridman O, Gefen O, Balaban NQ. Distinguishing between resistance, tolerance and persistence to antibiotic treatment. Nat Rev Microbiol. 2016;14(5):320–30.CrossRefGoogle Scholar
  58. 58.
    Frimodt-Moller N. Correlation between pharmacokinetic/pharmacodynamic parameters and efficacy for antibiotics in the treatment of urinary tract infection. Int J Antimicrob Agents. 2002;19(6):546–53.PubMedCrossRefPubMedCentralGoogle Scholar
  59. 59.
    Mueller M, de la Pena A, Derendorf H. Issues in pharmacokinetics and pharmacodynamics of anti-infective agents: kill curves versus MIC. Antimicrob Agents Chemother. 2004;48(2):369–77.PubMedPubMedCentralCrossRefGoogle Scholar
  60. 60.
    Balaban NQ, Merrin J, Chait R, Kowalik L, Leibler S. Bacterial persistence as a phenotypic switch. Science. 2004;305(5690):1622–5.CrossRefGoogle Scholar
  61. 61.
    Wakamoto Y, Dhar N, Chait R, Schneider K, Signorino-Gelo F, Leibler S, et al. Dynamic persistence of antibiotic-stressed mycobacteria. Science. 2013;339(6115):91–5.PubMedCrossRefGoogle Scholar
  62. 62.
    Orman MA, Brynildsen MP. Dormancy is not necessary or sufficient for bacterial persistence. Antimicrob Agents Chemother. 2013;57(7):3230–9.PubMedPubMedCentralCrossRefGoogle Scholar
  63. 63.
    Stewart B, Rozen DE. Genetic variation for antibiotic persistence in Escherichia coli. Evolution. 2012;66(3):933–9.PubMedCrossRefGoogle Scholar
  64. 64.
    Amato SM, Brynildsen MP. Persister heterogeneity arising from a single metabolic stress. Curr Biol. 2015;25(16):2090–8.PubMedCrossRefGoogle Scholar
  65. 65.
    Su HW, Zhu JH, Li H, Cai RJ, Ealand C, Wang X, et al. The essential mycobacterial amidotransferase GatCAB is a modulator of specific translational fidelity. Nat Microbiol. 2016;1(11):16147.PubMedCrossRefGoogle Scholar
  66. 66.
    Lewis K, Shan Y. Why tolerance invites reistance. Science. 2017;355:796.PubMedCrossRefGoogle Scholar
  67. 67.
    de Carvalho LP, Darby CM, Rhee KY, Nathan C. Nitazoxanide disrupts membrane potential and intrabacterial pH homeostasis of Mycobacterium tuberculosis. ACS Med Chem Lett. 2011;2(11):849–54.PubMedPubMedCentralCrossRefGoogle Scholar
  68. 68.
    Venugopal A, Bryk R, Shi S, Rhee K, Rath P, Schnappinger D, et al. Virulence of Mycobacterium tuberculosis depends on lipoamide dehydrogenase, a member of three multienzyme complexes. Cell Host Microbe. 2011;9(1):21–31.PubMedPubMedCentralCrossRefGoogle Scholar
  69. 69.
    Darby CM, Ingolfsson HI, Jiang X, Shen C, Sun M, Zhao N, et al. Whole cell screen for inhibitors of pH homeostasis in Mycobacterium tuberculosis. PLoS One. 2013;8(7):e68942.PubMedPubMedCentralCrossRefGoogle Scholar
  70. 70.
    Schnappinger D, Ehrt S, Voskuil MI, Liu Y, Mangan JA, Monahan IM, et al. Transcriptional adaptation of Mycobacterium tuberculosis within macrophages: insights into the phagosomal environment. J Exp Med. 2003;198(5):693–704.PubMedPubMedCentralCrossRefGoogle Scholar
  71. 71.
    Voskuil MI, Schnappinger D, Visconti KC, Harrell MI, Dolganov GM, Sherman DR, et al. Inhibition of respiration by nitric oxide induces a Mycobacterium tuberculosis dormancy program. J Exp Med. 2003;198(5):705–13.PubMedPubMedCentralCrossRefGoogle Scholar
  72. 72.
    Sarathy J, Dartois V, Dick T, Gengenbacher M. Reduced drug uptake in phenotypically resistant nutrient-starved nonreplicating Mycobacterium tuberculosis. Antimicrob Agents Chemother. 2013;57(4):1648–53.PubMedPubMedCentralCrossRefGoogle Scholar
  73. 73.
    Adams KN, Takaki K, Connolly LE, Wiedenhoft H, Winglee K, Humbert O, et al. Drug tolerance in replicating mycobacteria mediated by a macrophage-induced efflux mechanism. Cell. 2011;145(1):39–53.PubMedPubMedCentralCrossRefGoogle Scholar
  74. 74.
    Giddey AD, de Kock E, Nakedi KC, Garnett S, Nel AJ, Soares NC, et al. A temporal proteome dynamics study reveals the molecular basis of induced phenotypic resistance in Mycobacterium smegmatis at sub-lethal rifampicin concentrations. Sci Rep. 2017;7:43858.PubMedPubMedCentralCrossRefGoogle Scholar
  75. 75.
    Kohanski MA, Dwyer DJ, Hayete B, Lawrence CA, Collins JJ. A common mechanism of cellular death induced by bactericidal antibiotics. Cell. 2007;130(5):797–810.PubMedCrossRefPubMedCentralGoogle Scholar
  76. 76.
    Nandakumar M, Nathan C, Rhee KY. Isocitrate lyase mediates broad antibiotic tolerance in Mycobacterium tuberculosis. Nat Commun. 2014;5:4306.PubMedCrossRefPubMedCentralGoogle Scholar
  77. 77.
    Harms A, Maisonneuve E, Gerdes K. Mechanisms of bacterial persistence during stress and antibiotic exposure. Science. 2016;354(6318)PubMedCrossRefGoogle Scholar
  78. 78.
    Jankevicius G, Ariza A, Ahel M, Ahel I. The toxin-antitoxin system DarTG catalyzes reversible ADP-ribosylation of DNA. Mol Cell. 2016;64(6):1109–16.PubMedPubMedCentralCrossRefGoogle Scholar
  79. 79.
    Beckert B, Abdelshahid M, Schafer H, Steinchen W, Arenz S, Berninghausen O, et al. Structure of the Bacillus subtilis hibernating 100S ribosome reveals the basis for 70S dimerization. EMBO J. 2017;Google Scholar
  80. 80.
    Rath P, Huang C, Wang T, Wang T, Li H, Prados-Rosales R, et al. Genetic regulation of vesiculogenesis and immunomodulation in Mycobacterium tuberculosis. Proc Natl Acad Sci U S A. 2013;110(49):E4790–7.PubMedPubMedCentralCrossRefGoogle Scholar
  81. 81.
    Bryk R, Gold B, Venugopal A, Singh J, Samy R, Pupek K, et al. Selective killing of nonreplicating mycobacteria. Cell Host Microbe. 2008;3(3):137–45.PubMedPubMedCentralCrossRefGoogle Scholar
  82. 82.
    Bryk R, Griffin P, Nathan C. Peroxynitrite reductase activity of bacterial peroxiredoxins. Nature. 2000;407(6801):211–5.PubMedCrossRefGoogle Scholar
  83. 83.
    Bryk R, Lima CD, Erdjument-Bromage H, Tempst P, Nathan C. Metabolic enzymes of mycobacteria linked to antioxidant defense by a thioredoxin-like protein. Science. 2002;295(5557):1073–7.PubMedCrossRefGoogle Scholar
  84. 84.
    Maksymiuk C, Balakrishnan A, Bryk R, Rhee KY, Nathan CF. E1 of alpha-ketoglutarate dehydrogenase defends Mycobacterium tuberculosis against glutamate anaplerosis and nitroxidative stress. Proc Natl Acad Sci U S A. 2015;112(43):E5834–43.PubMedPubMedCentralCrossRefGoogle Scholar
  85. 85.
    Vandal OH, Pierini LM, Schnappinger D, Nathan CF, Ehrt S. A membrane protein preserves intrabacterial pH in intraphagosomal Mycobacterium tuberculosis. Nat Med. 2008;14(8):849–54.PubMedPubMedCentralCrossRefGoogle Scholar
  86. 86.
    Darwin KH, Nathan CF. Role for nucleotide excision repair in virulence of Mycobacterium tuberculosis. Infect Immun. 2005;73(8):4581–7.PubMedPubMedCentralCrossRefGoogle Scholar
  87. 87.
    Darwin KH, Ehrt S, Gutierrez-Ramos JC, Weich N, Nathan CF. The proteasome of Mycobacterium tuberculosis is required for resistance to nitric oxide. Science. 2003;302(5652):1963–6.PubMedCrossRefGoogle Scholar
  88. 88.
    Lin G, Li D, de Carvalho LP, Deng H, Tao H, Vogt G, et al. Inhibitors selective for mycobacterial versus human proteasomes. Nature. 2009;461(7264):621–6.PubMedPubMedCentralCrossRefGoogle Scholar
  89. 89.
    Vaubourgeix J, Lin G, Dhar N, Chenouard N, Jiang X, Botella H, et al. Stressed mycobacteria use the chaperone ClpB to sequester irreversibly oxidized proteins asymmetrically within and between cells. Cell Host Microbe. 2015;17(2):178–90.PubMedPubMedCentralCrossRefGoogle Scholar
  90. 90.
    Bryk R, Arango N, Maksymiuk C, Balakrishnan A, Wu YT, Wong CH, et al. Lipoamide channel-binding sulfonamides selectively inhibit mycobacterial lipoamide dehydrogenase. Biochemistry. 2013;52(51):9375–84.PubMedPubMedCentralCrossRefGoogle Scholar
  91. 91.
    Bryk R, Arango N, Venugopal A, Warren JD, Park YH, Patel MS, et al. Triazaspirodimethoxybenzoyls as selective inhibitors of mycobacterial lipoamide dehydrogenase. Biochemistry. 2010;49(8):1616–27.PubMedPubMedCentralCrossRefGoogle Scholar
  92. 92.
    Lin G, Chidawanyika T, Tsu C, Warrier T, Vaubourgeix J, Blackburn C, et al. N,C-capped dipeptides with selectivity for mycobacterial proteasome over human proteasomes: role of S3 and S1 binding pockets. J Am Chem Soc. 2013;135(27):9968–71.PubMedPubMedCentralCrossRefGoogle Scholar
  93. 93.
    Gold B, Roberts J, Ling Y, Quezada LL, Glasheen J, Ballinger E, et al. Rapid, semiquantitative assay to discriminate among compounds with activity against replicating or nonreplicating Mycobacterium tuberculosis. Antimicrob Agents Chemother. 2015;59(10):6521–38.PubMedPubMedCentralCrossRefGoogle Scholar
  94. 94.
    Russo F, Gising J, Akerbladh L, Roos AK, Naworyta A, Mowbray SL, et al. Optimization and evaluation of 5-Styryl-Oxathiazol-2-one Mycobacterium tuberculosis proteasome inhibitors as Potential Antitubercular Agents. ChemistryOpen. 2015;4(3):342–62.PubMedPubMedCentralCrossRefGoogle Scholar
  95. 95.
    Warrier T, Martinez-Hoyos M, Marin-Amieva M, Colmenarejo G, Porras-De Francisco E, Alvarez-Pedraglio AI, et al. Identification of novel anti-mycobacterial compounds by screening a pharmaceutical small-molecule library against nonreplicating Mycobacterium tuberculosis. ACS Infect Dis. 2015;1(12):580–5.PubMedCrossRefGoogle Scholar
  96. 96.
    Gold B, Smith R, Nguyen Q, Roberts J, Ling Y, Lopez Quezada L, et al. Novel cephalosporins selectively active on nonreplicating Mycobacterium tuberculosis. J Med Chem. 2016;59(13):6027–44.PubMedPubMedCentralCrossRefGoogle Scholar
  97. 97.
    Darby CM, Nathan CF. Killing of non-replicating Mycobacterium tuberculosis by 8-hydroxyquinoline. J Antimicrob Chemother. 2010;65(7):1424–7.PubMedCrossRefGoogle Scholar
  98. 98.
    Shah S, Dalecki AG, Malalasekera AP, Crawford CL, Michalek SM, Kutsch O, et al. 8-Hydroxyquinolines are boosting agents of copper-related toxicity in Mycobacterium tuberculosis. Antimicrob Agents Chemother. 2016;60(10):5765–76.PubMedPubMedCentralCrossRefGoogle Scholar
  99. 99.
    Singh R, Manjunatha U, Boshoff HI, Ha YH, Niyomrattanakit P, Ledwidge R, et al. PA-824 kills nonreplicating Mycobacterium tuberculosis by intracellular NO release. Science. 2008;322(5906):1392–5.PubMedPubMedCentralCrossRefGoogle Scholar
  100. 100.
    Nathan C. An antibiotic mimics immunity. Science. 2008;322(5906):1337–8.PubMedCrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of Microbiology and ImmunologyWeill Cornell MedicineNew YorkUSA

Personalised recommendations