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Drug Susceptibility of Individual Mycobacterial Cells

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Persister Cells and Infectious Disease

Abstract

Mycobacterium tuberculosis causes the world’s deadliest infectious disease. Part of the pathogen’s success is its ability to diversify itself phenotypically and survive antibiotic therapy even in the absence of genetic resistance. Here, we will highlight the physiological aspects of the pathogen that promote tolerance and describe the mechanisms by which some of these vary in a genetically identical population. A better, molecular, understanding of this phenomenon may provide the key to improved TB therapy.

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References

  • Adams, K. N., Takaki, K., Connolly, L. E., Wiedenhoft, H., Winglee, K., Humbert, O., Edelstein, P. H., Cosma, C. L., & Ramakrishnan, L. (2011). Drug tolerance in replicating mycobacteria mediated by a macrophage-induced efflux mechanism. Cell, 145, 39–53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Adams, K. N., Szumowski, J. D., & Ramakrishnan, L. (2014). Verapamil, and its metabolite norverapamil, inhibit macrophage-induced, bacterial efflux pump-mediated tolerance to multiple anti-tubercular drugs. Journal of Infectious Diseases, 210, 456–466.

    Article  CAS  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Aldridge, B. B., Keren, I., & Fortune, S. M. (2014). The spectrum of drug susceptibility in mycobacteria. Microbiology Spectrum, 2, 1–14.

    Article  CAS  Google Scholar 

  • Balaban, N. Q., Merrin, J., Chait, R., Kowalik, L., & Leibler, S. (2004). Bacterial persistence as a phenotypic switch. Science, 305, 1622–1625.

    Article  CAS  PubMed  Google Scholar 

  • Balaban, N. Q., Gerdes, K., Lewis, K., & Mckinney, J. D. (2013). A problem of persistence: Still more questions than answers? Nature Reviews Microbiology, 11, 587–591.

    Article  CAS  PubMed  Google Scholar 

  • Balazsi, G., Heath, A. P., Shi, L., & Gennaro, M. L. (2008). The temporal response of the Mycobacterium tuberculosis gene regulatory network during growth arrest. Molecular Systems Biology, 4, 225.

    Article  PubMed  PubMed Central  Google Scholar 

  • Balganesh, M., Dinesh, N., Sharma, S., Kuruppath, S., Nair, A. V., & Sharma, U. (2012). Efflux pumps of Mycobacterium tuberculosis play a significant role in antituberculosis activity of potential drug candidates. Antimicrobial Agents and Chemotherapy, 56, 2643–2651.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Baranowski, C., Sham, L.-T., Eskandarian, H. A., Welsh, M. A., Lim, H. C., Kieser, K. J., Wagner, J. C., Walker, S., Mckinney, J. D., Fantner, G. E., Ioerger, T. R., Bernhardt, T. G., Rubin, E. J., & Rego, E. H. (2018). Maturing Mycobacterium smegmatis peptidoglycan requires non-canonical crosslinks to maintain shape. eLife, 7:e37516

    Google Scholar 

  • Bayliss, C. D. (2009). Determinants of phase variation rate and the fitness implications of differing rates for bacterial pathogens and commensals. FEMS Microbiology Reviews, 33, 504–520.

    Article  CAS  PubMed  Google Scholar 

  • Baysarowich, J., Koteva, K., Hughes, D. W., Ejim, L., Griffiths, E., Zhang, K., Junop, M., & Wright, G. D. (2008). Rifamycin antibiotic resistance by ADP-ribosylation: Structure and diversity of Arr. Proceedings of the National Academy of Sciences of the United States of America, 105, 4886–4891.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Betts, J. C., Lukey, P. T., Robb, L. C., Mcadam, R. A., & Duncan, K. (2002). Evaluation of a nutrient starvation model of Mycobacterium tuberculosis persistence by gene and protein expression profiling. Molecular Microbiology, 43, 717–731.

    Article  CAS  PubMed  Google Scholar 

  • Bhaskar, A., De Piano, C., Gelman, E., Mckinney, J. D., & Dhar, N. (2018). Elucidating the role of (p)ppGpp in mycobacterial persistence against antibiotics. IUBMB Life, 70, 836–844.

    Article  CAS  PubMed  Google Scholar 

  • Boot, M., Sparrius, M., Jim, K. K., Commandeur, S., Speer, A., van de Weerd, R., & Bitter, W. (2016). iniBAC induction Is Vitamin B12- and MutAB-dependent in Mycobacterium marinum. The Journal of Biological Chemistry, 291, 19800–19812.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Boot, M., van Winden, V. J. C., Sparrius, M., van de Weerd, R., Speer, A., Ummels, R., Rustad, T., Sherman, D. R., & Bitter, W. (2017). Cell envelope stress in mycobacteria is regulated by the novel signal transduction ATPase IniR in response to trehalose. PLoS Genetics, 13, e1007131.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Boot, M., Commandeur, S., Subudhi, A. K., Bahira, M., Smith, T. C., 2nd, Abdallah, A. M., van Gemert, M., Lelievre, J., Ballell, L., Aldridge, B. B., Pain, A., Speer, A., & Bitter, W. (2018). Accelerating early antituberculosis drug discovery by creating mycobacterial indicator strains that predict mode of action. Antimicrobial Agents and Chemotherapy, 62.

    Google Scholar 

  • Boshoff, H. I., & Barry, C. E., 3rd. (2005). Tuberculosis – metabolism and respiration in the absence of growth. Nature Reviews. Microbiology, 3, 70–80.

    Article  CAS  PubMed  Google Scholar 

  • Boshoff, H. I., Myers, T. G., Copp, B. R., Mcneil, M. R., Wilson, M. A., Barry, C. E., & 3RD. (2004). The transcriptional responses of Mycobacterium tuberculosis to inhibitors of metabolism: Novel insights into drug mechanisms of action. The Journal of Biological Chemistry, 279, 40174–40184.

    Article  CAS  PubMed  Google Scholar 

  • Boutte, C. C., & Crosson, S. (2013). Bacterial lifestyle shapes stringent response activation. Trends in Microbiology, 21, 174–180.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Boutte, C. C., Baer, C. E., Papavinasasundaram, K., Liu, W., Chase, M. R., Meniche, X., Fortune, S. M., Sassetti, C. M., Ioerger, T. R., & Rubin, E. J. (2016). A cytoplasmic peptidoglycan amidase homologue controls mycobacterial cell wall synthesis. eLife, 5.

    Google Scholar 

  • Brauner, A., Fridman, O., Gefen, O., & Balaban, N. Q. (2016). Distinguishing between resistance, tolerance and persistence to antibiotic treatment. Nature Reviews Microbiology, 14, 320–330.

    Article  CAS  PubMed  Google Scholar 

  • Brennan, P. J., & Nikaido, H. (1995). The envelope of mycobacteria. Annual Review of Biochemistry, 64, 29–63.

    Article  CAS  PubMed  Google Scholar 

  • Brown, B. A., Wallace, R. J., Jr., Onyi, G. O., de Rosas, V., & Wallace, R. J., 3rd. (1992). Activities of four macrolides, including clarithromycin, against Mycobacterium fortuitum, Mycobacterium chelonae, and M. chelonae-like organisms. Antimicrobial Agents and Chemotherapy, 36, 180–184.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bryk, R., Gold, B., Venugopal, A., Singh, J., Samy, R., Pupek, K., Cao, H., Popescu, C., Gurney, M., Hotha, S., Cherian, J., Rhee, K., Ly, L., Converse, P. J., Ehrt, S., Vandal, O., Jiang, X., Schneider, J., Lin, G., & Nathan, C. (2008). Selective killing of nonreplicating mycobacteria. Cell Host & Microbe, 3, 137–145.

    Article  CAS  Google Scholar 

  • Buchanan, S. K. (2001). Type I secretion and multidrug efflux: Transport through the TolC channel-tunnel. Trends in Biochemical Sciences, 26, 3–6.

    Article  CAS  PubMed  Google Scholar 

  • Buriankova, K., Doucet-Populaire, F., Dorson, O., Gondran, A., Ghnassia, J. C., Weiser, J., & Pernodet, J. L. (2004). Molecular basis of intrinsic macrolide resistance in the Mycobacterium tuberculosis complex. Antimicrobial Agents and Chemotherapy, 48, 143–150.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Buroni, S., Manina, G., Guglierame, P., Pasca, M. R., Riccardi, G., & de Rossi, E. (2006). LfrR is a repressor that regulates expression of the efflux pump LfrA in Mycobacterium smegmatis. Antimicrobial Agents and Chemotherapy, 50, 4044–4052.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cadena, A. M., Fortune, S. M., & Flynn, J. L. (2017). Heterogeneity in tuberculosis. Nature Reviews Immunology, 17, 691–702.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Caleffi-Ferracioli, K. R., Amaral, R. C., Demitto, F. O., Maltempe, F. G., Canezin, P. H., Scodro, R. B., Nakamura, C. V., Leite, C. Q., Siqueira, V. L., & Cardoso, R. F. (2016). Morphological changes and differentially expressed efflux pump genes in Mycobacterium tuberculosis exposed to a rifampicin and verapamil combination. Tuberculosis (Edinburgh, Scotland), 97, 65–72.

    Article  CAS  Google Scholar 

  • Carey, L. B. (2015). RNA polymerase errors cause splicing defects and can be regulated by differential expression of RNA polymerase subunits. Elife, 4, e09945.

    Article  PubMed  PubMed Central  Google Scholar 

  • Chaudhuri, S., Li, L., Zimmerman, M., Chen, Y., Chen, Y. X., Toosky, M. N., Gardner, M., Pan, M., Li, Y. Y., Kawaji, Q., Zhu, J. H., Su, H. W., Martinot, A. J., Rubin, E. J., Dartois, V. A., & Javid, B. (2018). Kasugamycin potentiates rifampicin and limits emergence of resistance in Mycobacterium tuberculosis by specifically decreasing mycobacterial mistranslation. eLife, 7, e36782.

    Article  PubMed  PubMed Central  Google Scholar 

  • Colangeli, R., Helb, D., Sridharan, S., Sun, J., Varma-Basil, M., Hazbon, M. H., Harbacheuski, R., Megjugorac, N. J., Jacobs, W. R., Jr., Holzenburg, A., Sacchettini, J. C., & 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. Molecular Microbiology, 55, 1829–1840.

    Article  CAS  PubMed  Google Scholar 

  • Conlon, B. P., Rowe, S. E., Gandt, A. B., Nuxoll, A. S., Donegan, N. P., Zalis, E. A., Clair, G., Adkins, J. N., Cheung, A. L., & Lewis, K. (2016). Persister formation in Staphylococcus aureus is associated with ATP depletion. Nature Microbiology, 1, 16051.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • da Silva, P. E., von Groll, A., Martin, A., & Palomino, J. C. (2011). Efflux as a mechanism for drug resistance in Mycobacterium tuberculosis. FEMS Immunology and Medical Microbiology, 63, 1–9.

    Article  PubMed  CAS  Google Scholar 

  • da Silva, P. E., Machado, D., Ramos, D., Couto, I., von Groll, A., & Viveiros, M. (2016). Efflux pumps in mycobacteria: Antimicrobial resistance, physiological functions, and role in pathogenicity. In X. Z. Li (Ed.), Efflux-mediated antimicrobial resistance in bacteria. Cham: Springer.

    Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Dar, R. D., Hosmane, N. N., Arkin, M. R., Siliciano, R. F., & Weinberger, L. S. (2014). Screening for noise in gene expression identifies drug synergies. Science, 344, 1392–1396.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • de Rossi, E., Ainsa, J. A., & Riccardi, G. (2006). Role of mycobacterial efflux transporters in drug resistance: An unresolved question. FEMS Microbiology Reviews, 30, 36–52.

    Article  PubMed  CAS  Google Scholar 

  • de Steenwinkel, J. E., de Knegt, G. J., ten Kate, M. T., van Belkum, A., Verbrugh, H. A., Kremer, K., van Soolingen, D., & Bakker-Woudenberg, I. A. (2010). Time-kill kinetics of anti-tuberculosis drugs, and emergence of resistance, in relation to metabolic activity of Mycobacterium tuberculosis. The Journal of Antimicrobial Chemotherapy, 65, 2582–2589.

    Article  PubMed  CAS  Google Scholar 

  • Diacon, A. H., van der Merwe, L., Barnard, M., von Groote-Bidlingmaier, F., Lange, C., Garcia-Basteiro, A. L., Sevene, E., Ballell, L., & Barros-Aguirre, D. (2016). beta-lactams against tuberculosis – New trick for an old dog? The New England Journal of Medicine, 375, 393–394.

    Article  PubMed  Google Scholar 

  • Dinesh, N., Sharma, S., & Balganesh, M. (2013). Involvement of efflux pumps in the resistance to peptidoglycan synthesis inhibitors in Mycobacterium tuberculosis. Antimicrobial Agents and Chemotherapy, 57, 1941–1943.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Doerks, T., van Noort, V., Minguez, P., & Bork, P. (2012). Annotation of the M. tuberculosis hypothetical orfeome: Adding functional information to more than half of the uncharacterized proteins. PLoS One, 7, e34302.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Dorr, T., Vulic, M., & Lewis, K. (2010). Ciprofloxacin causes persister formation by inducing the TisB toxin in Escherichia coli. PLoS Biology, 8, e1000317.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Dye, C. (2006). Global epidemiology of tuberculosis. Lancet, 367, 938–940.

    Article  PubMed  Google Scholar 

  • el Meouche, I., Siu, Y., & Dunlop, M. J. (2016). Stochastic expression of a multiple antibiotic resistance activator confers transient resistance in single cells. Scientific Reports, 6, 19538.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Eldar, A., & Elowitz, M. B. (2010). Functional roles for noise in genetic circuits. Nature, 467, 167–173.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Eskandarian, H. A., Odermatt, P. D., Ven, J. X. Y., Hannebelle, M. T. M., Nievergelt, A. P., Dhar, N., Mckinney, J. D., & Fantner, G. E. (2017). Division site selection linked to inherited cell surface wave troughs in mycobacteria. Nature Microbiology, 2, 17094.

    Article  CAS  PubMed  Google Scholar 

  • Evans, D. J., Allison, D. G., Brown, M. R., & Gilbert, P. (1991). Susceptibility of Pseudomonas aeruginosa and Escherichia coli biofilms towards ciprofloxacin: Effect of specific growth rate. The Journal of Antimicrobial Chemotherapy, 27, 177–184.

    Article  CAS  PubMed  Google Scholar 

  • Ferullo, D. J., & Lovett, S. T. (2008). The stringent response and cell cycle arrest in Escherichia coli. PLoS Genetics, 4, e1000300.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Finch, R. (1986). Beta-lactam antibiotics and mycobacteria. The Journal of Antimicrobial Chemotherapy, 18, 6–8.

    Article  CAS  PubMed  Google Scholar 

  • Fox, W., Ellard, G. A., & Mitchison, D. A. (1999). Studies on the treatment of tuberculosis undertaken by the British Medical Research Council tuberculosis units, 1946-1986, with relevant subsequent publications. The International Journal of Tuberculosis and Lung Disease, 3, S231–S279.

    CAS  PubMed  Google Scholar 

  • Gefen, O., Gabay, C., Mumcuoglu, M., Engel, G., & Balaban, N. Q. (2008). Single-cell protein induction dynamics reveals a period of vulnerability to antibiotics in persister bacteria. Proceedings of the National Academy of Sciences of the United States of America, 105, 6145–6149.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gengenbacher, M., Rao, S. P., Pethe, K., & Dick, T. (2010). Nutrient-starved, non-replicating Mycobacterium tuberculosis requires respiration, ATP synthase and isocitrate lyase for maintenance of ATP homeostasis and viability. Microbiology, 156, 81–87.

    Article  CAS  PubMed  Google Scholar 

  • Germain, E., Castro-Roa, D., Zenkin, N., & Gerdes, K. (2013). Molecular mechanism of bacterial persistence by HipA. Molecular Cell, 52, 248–254.

    Article  CAS  PubMed  Google Scholar 

  • Gill, W. P., Harik, N. S., Whiddon, M. R., Liao, R. P., Mittler, J. E., & Sherman, D. R. (2009). A replication clock for Mycobacterium tuberculosis. Nature Medicine, 15, 211–214.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Graham, L. L., Beveridge, T. J., & Nanninga, N. (1991). Periplasmic space and the concept of the periplasm. Trends in Biochemical Sciences, 16, 328–329.

    Article  CAS  PubMed  Google Scholar 

  • Grant, S. S., Kawate, T., Nag, P. P., Silvis, M. R., Gordon, K., Stanley, S. A., Kazyanskaya, E., Nietupski, R., Golas, A., Fitzgerald, M., Cho, S., Franzblau, S. G., & Hung, D. T. (2013). Identification of novel inhibitors of nonreplicating Mycobacterium tuberculosis using a carbon starvation model. ACS Chemical Biology, 8, 2224–2234.

    Article  CAS  PubMed  Google Scholar 

  • Gupta, A. K., Katoch, V. M., Chauhan, D. S., Sharma, R., Singh, M., Venkatesan, K., & Sharma, V. D. (2010). Microarray analysis of efflux pump genes in multidrug-resistant Mycobacterium tuberculosis during stress induced by common anti-tuberculous drugs. Microbial Drug Resistance, 16, 21–28.

    Article  CAS  PubMed  Google Scholar 

  • Haemers, A., Leysen, D. C., Bollaert, W., Zhang, M. Q., & Pattyn, S. R. (1990). Influence of N substitution on antimycobacterial activity of ciprofloxacin. Antimicrobial Agents and Chemotherapy, 34, 496–497.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Harms, A., Fino, C., Sorensen, M. A., Semsey, S., & Gerdes, K. (2017). Prophages and growth dynamics confound experimental results with antibiotic-tolerant persister cells. MBio, 8, e01964-17.

    Article  PubMed  PubMed Central  Google Scholar 

  • Hartman, T. E., Wang, Z., Jansen, R. S., Gardete, S., & Rhee, K. Y. (2017). Metabolic perspectives on persistence. Microbiology Spectrum, 5, TBTB2-0026-2016.

    Article  Google Scholar 

  • Heifets, L. B., Lindholm-Levy, P. J., & Flory, M. A. (1990). Bactericidal activity in vitro of various rifamycins against Mycobacterium avium and Mycobacterium tuberculosis. The American Review of Respiratory Disease, 141, 626–630.

    Article  CAS  PubMed  Google Scholar 

  • Herbert, D., Paramasivan, C. N., Venkatesan, P., Kubendiran, G., Prabhakar, R., & Mitchison, D. A. (1996). Bactericidal action of ofloxacin, sulbactam-ampicillin, rifampin, and isoniazid on logarithmic- and stationary-phase cultures of Mycobacterium tuberculosis. Antimicrobial Agents and Chemotherapy, 40, 2296–2299.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Heym, B., Zhang, Y., Poulet, S., Young, D., & Cole, S. T. (1993). Characterization of the katG gene encoding a catalase-peroxidase required for the isoniazid susceptibility of Mycobacterium tuberculosis. Journal of Bacteriology, 175, 4255–4259.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Heym, B., Alzari, P. M., Honore, N., & Cole, S. T. (1995). Missense mutations in the catalase-peroxidase gene, katG, are associated with isoniazid resistance in Mycobacterium tuberculosis. Molecular Microbiology, 15, 235–245.

    Article  CAS  PubMed  Google Scholar 

  • Hicks, N. D., Yang, J., Zhang, X., Zhao, B., Grad, Y. H., Liu, L., Ou, X., Chang, Z., Xia, H., Zhou, Y., Wang, S., Dong, J., Sun, L., Zhu, Y., Zhao, Y., Jin, Q., & Fortune, S. M. (2018). Clinically prevalent mutations in Mycobacterium tuberculosis alter propionate metabolism and mediate multidrug tolerance. Nature Microbiology, 3, 1032–1042.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ho, R. H., & Kim, R. B. (2005). Transporters and drug therapy: Implications for drug disposition and disease. Clinical Pharmacology and Therapeutics, 78, 260–277.

    Article  CAS  PubMed  Google Scholar 

  • Horsburgh, C. R., Jr., Barry, C. E., 3rd, & Lange, C. (2015). Treatment of tuberculosis. The New England Journal of Medicine, 373, 2149–2160.

    Article  CAS  PubMed  Google Scholar 

  • Howard, S. T., Rhoades, E., Recht, J., Pang, X., Alsup, A., Kolter, R., Lyons, C. R., & Byrd, T. F. (2006). Spontaneous reversion of Mycobacterium abscessus from a smooth to a rough morphotype is associated with reduced expression of glycopeptidolipid and reacquisition of an invasive phenotype. Microbiology, 152, 1581–1590.

    Article  CAS  PubMed  Google Scholar 

  • Huh, D., & Paulsson, J. (2011). Random partitioning of molecules at cell division. Proceedings of the National Academy of Sciences of the United States of America, 108, 15004–15009.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jackson, M. (2014). The mycobacterial cell envelope-lipids. Cold Spring Harbor Perspectives in Medicine, 4.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Jankute, M., Cox, J. A., Harrison, J., & Besra, G. S. (2015). Assembly of the mycobacterial cell wall. Annual Review of Microbiology, 69, 405–423.

    Article  CAS  PubMed  Google Scholar 

  • Javid, B., Sorrentino, F., Toosky, M., Zheng, W., Pinkham, J. T., Jain, N., Pan, M., Deighan, P., & Rubin, E. J. (2014). Mycobacterial mistranslation is necessary and sufficient for rifampicin phenotypic resistance. Proceedings of the National Academy of Sciences of the United States of America, 111, 1132–1137.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Joyce, G., Williams, K. J., Robb, M., Noens, E., Tizzano, B., Shahrezaei, V., & Robertson, B. D. (2012). Cell division site placement and asymmetric growth in mycobacteria. PLoS One, 7, e44582.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kardan Yamchi, J., Haeili, M., Gizaw Feyisa, S., Kazemian, H., Hashemi Shahraki, A., Zahednamazi, F., Imani Fooladi, A. A., & Feizabadi, M. M. (2015). Evaluation of efflux pump gene expression among drug susceptible and drug resistant strains of Mycobacterium tuberculosis from Iran. Infection, Genetics and Evolution, 36, 23–26.

    Article  CAS  PubMed  Google Scholar 

  • Kasik, J. E. (1965). The nature of mycobacterial penicillinase. The American Review of Respiratory Disease, 91, 117–119.

    Article  CAS  PubMed  Google Scholar 

  • Keren, I., Minami, S., Rubin, E., & Lewis, K. (2011). Characterization and transcriptome analysis of Mycobacterium tuberculosis persisters. MBio, 2, e00100–e00111.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Kester, J. C., & Fortune, S. M. (2014). Persisters and beyond: Mechanisms of phenotypic drug resistance and drug tolerance in bacteria. Critical Reviews in Biochemistry and Molecular Biology, 49, 91–101.

    Article  CAS  PubMed  Google Scholar 

  • Koul, A., Vranckx, L., Dendouga, N., Balemans, W., van den Wyngaert, I., Vergauwen, K., Gohlmann, H. W., Willebrords, R., Poncelet, A., Guillemont, J., Bald, D., & Andries, K. (2008). Diarylquinolines are bactericidal for dormant mycobacteria as a result of disturbed ATP homeostasis. The Journal of Biological Chemistry, 283, 25273–25280.

    Article  CAS  PubMed  Google Scholar 

  • Kunkel, T. A., & Bebenek, K. (2000). DNA replication fidelity. Annual Review of Biochemistry, 69, 497–529.

    Article  CAS  PubMed  Google Scholar 

  • Kysela, D. T., Brown, P. J., Huang, K. C., & Brun, Y. V. (2013). Biological consequences and advantages of asymmetric bacterial growth. Annual Review of Microbiology, 67, 417–435.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Li, X. Z., Nikaido, H., & Poole, K. (1995). Role of mexA-mexB-oprM in antibiotic efflux in Pseudomonas aeruginosa. Antimicrobial Agents and Chemotherapy, 39, 1948–1953.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Liu, Y., Tan, S., Huang, L., Abramovitch, R. B., Rohde, K. H., Zimmerman, M. D., Chen, C., Dartois, V., Vanderven, B. C., & Russell, D. G. (2016). Immune activation of the host cell induces drug tolerance in Mycobacterium tuberculosis both in vitro and in vivo. The Journal of Experimental Medicine, 213, 809–825.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Liu, S., Wu, N., Zhang, S., Yuan, Y., Zhang, W., & Zhang, Y. (2017). Variable persister gene interactions with (p)ppGpp for persister formation in Escherichia coli. Frontiers in Microbiology, 8, 1795.

    Article  PubMed  PubMed Central  Google Scholar 

  • Logsdon, M. M., & Aldridge, B. B. (2018). Stable regulation of cell cycle events in mycobacteria: Insights from inherently heterogeneous bacterial populations. Frontiers in Microbiology, 9, 514.

    Article  PubMed  PubMed Central  Google Scholar 

  • Ma, D., Cook, D. N., Alberti, M., Pon, N. G., Nikaido, H., & Hearst, J. E. (1993). Molecular cloning and characterization of acrA and acrE genes of Escherichia coli. Journal of Bacteriology, 175, 6299–6313.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mailaender, C., Reiling, N., Engelhardt, H., Bossmann, S., Ehlers, S., & Niederweis, M. (2004). The MspA porin promotes growth and increases antibiotic susceptibility of both Mycobacterium bovis BCG and Mycobacterium tuberculosis. Microbiology, 150, 853–864.

    Article  CAS  PubMed  Google Scholar 

  • Manina, G., Dhar, N., & Mckinney, J. D. (2015). Stress and host immunity amplify Mycobacterium tuberculosis phenotypic heterogeneity and induce nongrowing metabolically active forms. Cell Host & Microbe, 17, 32–46.

    Article  CAS  Google Scholar 

  • Martinot, A. J., Farrow, M., Bai, L., Layre, E., Cheng, T. Y., Tsai, J. H., Iqbal, J., Annand, J. W., Sullivan, Z. A., Hussain, M. M., Sacchettini, J., Moody, D. B., Seeliger, J. C., & Rubin, E. J. (2016). Mycobacterial metabolic syndrome: LprG and Rv1410 regulate triacylglyceride levels, growth rate and virulence in Mycobacterium tuberculosis. PLoS Pathogens, 12, e1005351.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Mcdaniel, M. M., Krishna, N., Handagama, W. G., Eda, S., & Ganusov, V. V. (2016). Quantifying limits on replication, death, and quiescence of Mycobacterium tuberculosis in mice. Frontiers in Microbiology, 7, 862.

    PubMed  PubMed Central  Google Scholar 

  • Mitchison, D., & Davies, G. (2012). The chemotherapy of tuberculosis: Past, present and future. The International Journal of Tuberculosis and Lung Disease, 16, 724–732.

    Article  CAS  PubMed  Google Scholar 

  • Mohler, K., & Ibba, M. (2017). Translational fidelity and mistranslation in the cellular response to stress. Nature Microbiology, 2, 17117.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Morris, R. P., Nguyen, L., Gatfield, J., Visconti, K., Nguyen, K., Schnappinger, D., Ehrt, S., Liu, Y., Heifets, L., Pieters, J., Schoolnik, G., & Thompson, C. J. (2005). Ancestral antibiotic resistance in Mycobacterium tuberculosis. Proceedings of the National Academy of Sciences of the United States of America, 102, 12200–12205.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Munoz-Elias, E. J., Timm, J., Botha, T., Chan, W. T., Gomez, J. E., & Mckinney, J. D. (2005). Replication dynamics of Mycobacterium tuberculosis in chronically infected mice. Infection and Immunity, 73, 546–551.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Murima, P., de Sessions, P. F., Lim, V., Naim, A. N., Bifani, P., Boshoff, H. I., Sambandamurthy, V. K., Dick, T., Hibberd, M. L., Schreiber, M., & Rao, S. P. (2013). Exploring the mode of action of bioactive compounds by microfluidic transcriptional profiling in mycobacteria. PLoS One, 8, e69191.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Nasiri, M. J., Haeili, M., Ghazi, M., Goudarzi, H., Pormohammad, A., Imani Fooladi, A. A., & Feizabadi, M. M. (2017). New insights in to the intrinsic and acquired drug resistance mechanisms in mycobacteria. Frontiers in Microbiology, 8, 681.

    Article  PubMed  PubMed Central  Google Scholar 

  • Nguyen, D., Joshi-Datar, A., Lepine, F., Bauerle, E., Olakanmi, O., Beer, K., Mckay, G., Siehnel, R., Schafhauser, J., Wang, Y., Britigan, B. E., & Singh, P. K. (2011). Active starvation responses mediate antibiotic tolerance in biofilms and nutrient-limited bacteria. Science, 334, 982–986.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Nikaido, H. (2001). Preventing drug access to targets: Cell surface permeability barriers and active efflux in bacteria. Seminars in Cell & Developmental Biology, 12, 215–223.

    Article  CAS  Google Scholar 

  • Niki, M., Niki, M., Tateishi, Y., Ozeki, Y., Kirikae, T., Lewin, A., Inoue, Y., Matsumoto, M., Dahl, J. L., Ogura, H., Kobayashi, K., & Matsumoto, S. (2012). A novel mechanism of growth phase-dependent tolerance to isoniazid in mycobacteria. The Journal of Biological Chemistry, 287, 27743–27752.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Paramasivan, C. N., Sulochana, S., Kubendiran, G., Venkatesan, P., & Mitchison, D. A. (2005). Bactericidal action of gatifloxacin, rifampin, and isoniazid on logarithmic- and stationary-phase cultures of Mycobacterium tuberculosis. Antimicrobial Agents and Chemotherapy, 49, 627–631.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Pawlik, A., Garnier, G., Orgeur, M., Tong, P., Lohan, A., le Chevalier, F., Sapriel, G., Roux, A. L., Conlon, K., Honore, N., Dillies, M. A., Ma, L., Bouchier, C., Coppee, J. Y., Gaillard, J. L., Gordon, S. V., Loftus, B., Brosch, R., & Herrmann, J. L. (2013). Identification and characterization of the genetic changes responsible for the characteristic smooth-to-rough morphotype alterations of clinically persistent Mycobacterium abscessus. Molecular Microbiology, 90, 612–629.

    Article  CAS  PubMed  Google Scholar 

  • Ramage, H. R., Connolly, L. E., & Cox, J. S. (2009). Comprehensive functional analysis of Mycobacterium tuberculosis toxin-antitoxin systems: Implications for pathogenesis, stress responses, and evolution. PLoS Genetics, 5, e1000767.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Rao, S. P., Alonso, S., Rand, L., Dick, T., & Pethe, K. (2008). The protonmotive force is required for maintaining ATP homeostasis and viability of hypoxic, nonreplicating Mycobacterium tuberculosis. Proceedings of the National Academy of Sciences of the United States of America, 105, 11945–11950.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Rego, E. H., Audette, R. E., & Rubin, E. J. (2017). Deletion of a mycobacterial divisome factor collapses single-cell phenotypic heterogeneity. Nature, 546, 153–157.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Richardson, K., Bennion, O. T., Tan, S., Hoang, A. N., Cokol, M., & Aldridge, B. B. (2016). Temporal and intrinsic factors of rifampicin tolerance in mycobacteria. Proceedings of the National Academy of Sciences of the United States of America, 113, 8302–8307.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Rittershaus, E. S., Baek, S. H., & Sassetti, C. M. (2013). The normalcy of dormancy: Common themes in microbial quiescence. Cell Host & Microbe, 13, 643–651.

    Article  CAS  Google Scholar 

  • Rodriguez-Rivera, F. P., Zhou, X., Theriot, J. A., & Bertozzi, C. R. (2017). Visualization of mycobacterial membrane dynamics in live cells. Journal of the American Chemical Society, 139, 3488–3495.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Russell, D. G. (2007). Who puts the tubercle in tuberculosis? Nature Reviews Microbiology, 5, 39–47.

    Article  CAS  PubMed  Google Scholar 

  • Sakatos, A., Babunovic, G. H., Chase, M. R., Dills, A., Leszyk, J., Rosebrock, T., Bryson, B., & Fortune, S. M. (2018). Posttranslational modification of a histone-like protein regulates phenotypic resistance to isoniazid in mycobacteria. Science Advances, 4, eaao1478.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Sala, A., Bordes, P., & Genevaux, P. (2014). Multiple toxin-antitoxin systems in Mycobacterium tuberculosis. Toxins (Basel), 6, 1002–1020.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Sarathy, J. P., Dartois, V., & Lee, E. J. (2012). The role of transport mechanisms in Mycobacterium tuberculosis drug resistance and tolerance. Pharmaceuticals (Basel), 5, 1210–1235.

    Article  CAS  Google Scholar 

  • Sarathy, J., Dartois, V., Dick, T., & Gengenbacher, M. (2013). Reduced drug uptake in phenotypically resistant nutrient-starved nonreplicating Mycobacterium tuberculosis. Antimicrobial Agents and Chemotherapy, 57, 1648–1653.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Schultz, D., Palmer, A. C., & Kishony, R. (2017). Regulatory dynamics determine cell fate following abrupt antibiotic exposure. Cell Systems, 5, 509–517.e3.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sherman, D. R., Voskuil, M., Schnappinger, D., Liao, R., Harrell, M. I., & Schoolnik, G. K. (2001). Regulation of the Mycobacterium tuberculosis hypoxic response gene encoding alpha -crystallin. Proceedings of the National Academy of Sciences of the United States of America, 98, 7534–7539.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Song, H., Sandie, R., Wang, Y., Andrade-Navarro, M. A., & Niederweis, M. (2008). Identification of outer membrane proteins of Mycobacterium tuberculosis. Tuberculosis (Edinburgh, Scotland), 88, 526–544.

    Article  CAS  Google Scholar 

  • Stahl, C., Kubetzko, S., Kaps, I., Seeber, S., Engelhardt, H., & Niederweis, M. (2001). MspA provides the main hydrophilic pathway through the cell wall of Mycobacterium smegmatis. Molecular Microbiology, 40, 451–464.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Su, H. W., Zhu, J. H., Li, H., Cai, R. J., Ealand, C., Wang, X., Chen, Y. X., Kayani, M. U., Zhu, T. F., Moradigaravand, D., Huang, H., Kana, B. D., & Javid, B. (2016). The essential mycobacterial amidotransferase GatCAB is a modulator of specific translational fidelity. Nature Microbiology, 1, 16147.

    Article  CAS  PubMed  Google Scholar 

  • Sureka, K., Ghosh, B., Dasgupta, A., Basu, J., Kundu, M., & Bose, I. (2008). Positive feedback and noise activate the stringent response regulator rel in mycobacteria. PLoS One, 3, e1771.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Taniguchi, Y., Choi, P. J., Li, G. W., Chen, H., Babu, M., Hearn, J., Emili, A., & Xie, X. S. (2010). Quantifying E. coli proteome and transcriptome with single-molecule sensitivity in single cells. Science, 329, 533–538.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • te Brake, L. H. M., de Knegt, G. J., de Steenwinkel, J. E., van Dam, T. J. P., Burger, D. M., Russel, F. G. M., van Crevel, R., Koenderink, J. B., & Aarnoutse, R. E. (2018). The role of efflux pumps in tuberculosis treatment and their promise as a target in drug development: Unraveling the black box. Annual Review of Pharmacology and Toxicology, 58, 271–291.

    Article  CAS  Google Scholar 

  • Thayil, S. M., Morrison, N., Schechter, N., Rubin, H., & Karakousis, P. C. (2011). The role of the novel exopolyphosphatase MT0516 in Mycobacterium tuberculosis drug tolerance and persistence. PLoS One, 6, e28076.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tiwari, A., Balazsi, G., Gennaro, M. L., & Igoshin, O. A. (2010). The interplay of multiple feedback loops with post-translational kinetics results in bistability of mycobacterial stress response. Physical Biology, 7, 036005.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Torrey, H. L., Keren, I., Via, L. E., Lee, J. S., & Lewis, K. (2016). High persister mutants in Mycobacterium tuberculosis. PLoS One, 11, e0155127.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Tuomanen, E., Cozens, R., Tosch, W., Zak, O., & Tomasz, A. (1986). The rate of killing of Escherichia coli by beta-lactam antibiotics is strictly proportional to the rate of bacterial growth. Journal of General Microbiology, 132, 1297–1304.

    CAS  PubMed  Google Scholar 

  • Vaubourgeix, J., Lin, G., Dhar, N., Chenouard, N., Jiang, X., Botella, H., Lupoli, T., Mariani, O., Yang, G., Ouerfelli, O., Unser, M., Schnappinger, D., Mckinney, J., & Nathan, C. (2015). Stressed mycobacteria use the chaperone ClpB to sequester irreversibly oxidized proteins asymmetrically within and between cells. Cell Host & Microbe, 17, 178–190.

    Article  CAS  Google Scholar 

  • Viveiros, M., Martins, M., Rodrigues, L., Machado, D., Couto, I., Ainsa, J., & Amaral, L. (2012). Inhibitors of mycobacterial efflux pumps as potential boosters for anti-tubercular drugs. Expert Review of Anti-Infective Therapy, 10, 983–998.

    Article  CAS  PubMed  Google Scholar 

  • Voskuil, M. I. (2004). Mycobacterium tuberculosis gene expression during environmental conditions associated with latency. Tuberculosis (Edinburgh, Scotland), 84, 138–143.

    Article  Google Scholar 

  • Wakamoto, Y., Dhar, N., Chait, R., Schneider, K., Signorino-Gelo, F., Leibler, S., & Mckinney, J. D. (2013). Dynamic persistence of antibiotic-stressed mycobacteria. Science, 339, 91–95.

    Article  CAS  PubMed  Google Scholar 

  • Wallace, R. J., Jr., Dalovisio, J. R., & Pankey, G. A. (1979). Disk diffusion testing of susceptibility of Mycobacterium fortuitum and Mycobacterium chelonei to antibacterial agents. Antimicrobial Agents and Chemotherapy, 16, 611–614.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Warrier, T., Martinez-Hoyos, M., Marin-Amieva, M., Colmenarejo, G., Porras-de Francisco, E., Alvarez-Pedraglio, A. I., Fraile-Gabaldon, M. T., Torres-Gomez, P. A., Lopez-Quezada, L., Gold, B., Roberts, J., Ling, Y., Somersan-Karakaya, S., Little, D., Cammack, N., Nathan, C., & Mendoza-Losana, A. (2015). Identification of novel anti-mycobacterial compounds by screening a pharmaceutical small-molecule library against nonreplicating Mycobacterium tuberculosis. ACS Infectious Diseases, 1, 580–585.

    Article  CAS  PubMed  Google Scholar 

  • Wayne, L. G., & Hayes, L. G. (1996). An in vitro model for sequential study of shiftdown of Mycobacterium tuberculosis through two stages of nonreplicating persistence. Infection and Immunity, 64, 2062–2069.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Wayne, L. G., & Lin, K. Y. (1982). Glyoxylate metabolism and adaptation of Mycobacterium tuberculosis to survival under anaerobic conditions. Infection and Immunity, 37, 1042–1049.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Wei, J. R., Krishnamoorthy, V., Murphy, K., Kim, J. H., Schnappinger, D., Alber, T., Sassetti, C. M., Rhee, K. Y., & Rubin, E. J. (2011). Depletion of antibiotic targets has widely varying effects on growth. Proceedings of the National Academy of Sciences of the United States of America, 108, 4176–4181.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • WHO. (2018). Global tuberculosis report.

    Google Scholar 

  • Xie, Z., Siddiqi, N., & Rubin, E. J. (2005). Differential antibiotic susceptibilities of starved Mycobacterium tuberculosis isolates. Antimicrobial Agents and Chemotherapy, 49, 4778–4780.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Xu, W., Dejesus, M. A., Rucker, N., Engelhart, C. A., Wright, M. G., Healy, C., Lin, K., Wang, R., Park, S. W., Ioerger, T. R., Schnappinger, D., & Ehrt, S. (2017a). Chemical genetic interaction profiling reveals determinants of intrinsic antibiotic resistance in Mycobacterium tuberculosis. Antimicrobial Agents and Chemotherapy, 61, e01334-17.

    Article  PubMed  PubMed Central  Google Scholar 

  • Xu, Z., Meshcheryakov, V. A., Poce, G., & Chng, S. S. (2017b). MmpL3 is the flippase for mycolic acids in mycobacteria. Proceedings of the National Academy of Sciences of the United States of America, 114, 7993–7998.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhang, B., Li, J., Yang, X., Wu, L., Zhang, J., Yang, Y., Zhao, Y., Zhang, L., Yang, X., Yang, X., Cheng, X., Liu, Z., Jiang, B., Jiang, H., Guddat, L. W., Yang, H., & Rao, Z. (2019). Crystal structures of membrane transporter MmpL3, an anti-TB drug target. Cell, 176, 636–648.e13.

    Article  CAS  PubMed  Google Scholar 

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  1. Department of Microbial Pathogenesis, Yale University School of Medicine, New Haven, CT, USA

    Maikel Boot & E. Hesper Rego

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    Kim Lewis

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Boot, M., Rego, E.H. (2019). Drug Susceptibility of Individual Mycobacterial Cells. In: Lewis, K. (eds) Persister Cells and Infectious Disease. Springer, Cham. https://doi.org/10.1007/978-3-030-25241-0_11

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