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Bacterial persistence: Fundamentals and clinical importance

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Abstract

The threat of antibiotic-resistant bacteria is increasing worldwide. Bacteria utilize persistence and resistance to survive antibiotic stress. For a long time, persistence has been studied only under laboratory conditions. Hence, studies of bacterial persistence are limited. Recently, however, the high incidence of infection relapses caused by persister cells in immunocompromised patients has emphasized the importance of persister research. Furthermore, persister pathogens are one of the causes of chronic infectious diseases, leading to the overuse of antibiotics and the emergence of antibiotic-resistant bacteria. Therefore, understanding the precise mechanism of persister formation is important for continued use of available antibiotics. In this review, we aimed to provide an overview of the persister studies published to date and the current knowledge of persister formation mechanisms. Recent studies of the features and mechanisms of persister formation are analyzed from the perspective of the nature of the persister cell.

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References

  • Baharoglu, Z. and Mazel, D. 2014. SOS, the formidable strategy of bacteria against aggressions. FEMS Microbiol. Rev. 38, 1126–1145.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Benveniste, R. and Davies, J. 1973. Mechanisms of antibiotic resistance in bacteria. Annu. Rev. Biochem. 42, 471–506.

    Article  CAS  PubMed  Google Scholar 

  • Bigger, J. 1944. Treatment of Staphylococcal infections with penicillin by intermittent sterilisation. Lancet 244, 497–500.

    Article  Google Scholar 

  • Black, D.S., Irwin, B., and Moyed, H.S. 1994. Autoregulation of hip, an operon that affects lethality due to inhibition of peptidoglycan or DNA synthesis. J. Bacteriol. 176, 4081–4091.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Black, D.S., Kelly, A.J., Mardis, M.J., and Moyed, H.S. 1991. Structure and organization of hip, an operon that affects lethality due to inhibition of peptidoglycan or DNA synthesis. J. Bacteriol. 173, 5732–5739.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Blair, J.M., Webber, M.A., Baylay, A.J., Ogbolu, D.O., and Piddock, L.J. 2015. Molecular mechanisms of antibiotic resistance. Nat. Rev. Microbiol. 13, 42–51.

    Article  CAS  PubMed  Google Scholar 

  • Brooun, A., Liu, S., and Lewis, K. 2000. A dose-response study of antibiotic resistance in Pseudomonas aeruginosa biofilms. Antimicrob. Agents Chemother. 44, 640–646.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Brown, M.R., Collier, P.J., and Gilbert, P. 1990. Influence of growth rate on susceptibility to antimicrobial agents: Modification of the cell envelope and batch and continuous culture studies. Antimicrob. Agents Chemother. 34, 1623–1628.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Christensen, S.K. and Gerdes, K. 2003. RelE toxins from Bacteria and Archaea cleave mRNAs on translating ribosomes, which are rescued by tmRNA. Mol. Microbiol. 48, 1389–1400.

    Article  CAS  PubMed  Google Scholar 

  • Dalebroux, Z.D. and Swanson, M.S. 2012. ppGpp: Magic beyond RNA polymerase. Nat. Rev. Microbiol. 10, 203–212.

    Article  CAS  PubMed  Google Scholar 

  • English, B.P., Hauryliuk, V., Sanamrad, A., Tankov, S., Dekker, N.H., and Elf, J. 2011. Single-molecule investigations of the stringent response machinery in living bacterial cells. Proc. Natl. Acad. Sci. USA 108, E365–373.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Guan, N., Li, J., Shin, H.D., Du, G., Chen, J., and Liu, L. 2017. Microbial response to environmental stresses: From fundamental mechanisms to practical applications. Appl. Microbiol. Biotechnol. 101, 3991–4008.

    Article  CAS  PubMed  Google Scholar 

  • Hansen, S., Vulic, M., Min, J., Yen, T.J., Schumacher, M.A., Brennan, R.G., and Lewis, K. 2012. Regulation of the Escherichia coli HipBA toxin-antitoxin system by proteolysis. PLoS One 7, e39185.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Harms, A., Maisonneuve, E., and Gerdes, K. 2016. Mechanisms of bacterial persistence during stress and antibiotic exposure. Science 354, aaf4268.

    Article  CAS  PubMed  Google Scholar 

  • Harrison, J.J., Ceri, H., Roper, N.J., Badry, E.A., Sproule, K.M., and Turner, R.J. 2005a. Persister cells mediate tolerance to metal oxyanions in Escherichia coli. Microbiology 151, 3181–3195.

    Article  CAS  PubMed  Google Scholar 

  • Harrison, J.J., Turner, R.J., and Ceri, H. 2005b. Persister cells, the biofilm matrix and tolerance to metal cations in biofilm and planktonic Pseudomonas aeruginosa. Environ. Microbiol. 7, 981–994.

    Article  CAS  PubMed  Google Scholar 

  • Hobby, G.L., Meyer, K., and Chaffee, E. 1942. Observations on the mechanism of action of penicillin. Proc. Soc. Exp. Biol. Med. 50, 281–285.

    Article  CAS  Google Scholar 

  • Hong, S.H., Wang, X., O’Connor, H.F., Benedik, M.J., and Wood, T.K. 2012. Bacterial persistence increases as environmental fitness decreases. Microb. Biotechnol. 5, 509–522.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hu, Y., Kwan, B.W., Osbourne, D.O., Benedik, M.J., and Wood, T.K. 2015. Toxin YafQ increases persister cell formation by reducing indole signalling. Environ. Microbiol. 17, 1275–1285.

    Article  CAS  PubMed  Google Scholar 

  • Joers, A., Kaldalu, N., and Tenson, T. 2010. The frequency of persisters in Escherichia coli reflects the kinetics of awakening from dormancy. J. Bacteriol. 192, 3379–3384.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Karkare, S. and Bhatnagar, D. 2006. Promising nucleic acid analogs and mimics: Characteristic features and applications of PNA, LNA, and morpholino. Appl. Microbiol. Biotechnol. 71, 575–586.

    Article  CAS  PubMed  Google Scholar 

  • Keren, I., Kaldalu, N., Spoering, A., Wang, Y., and Lewis, K. 2004a. Persister cells and tolerance to antimicrobials. FEMS Microbiol. Lett. 230, 13–18.

    Article  CAS  PubMed  Google Scholar 

  • Keren, I., Shah, D., Spoering, A., Kaldalu, N., and Lewis, K. 2004b. Specialized persister cells and the mechanism of multidrug tolerance in Escherichia coli. J. Bacteriol. 186, 8172–8180.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Khakimova, M., Ahlgren, H.G., Harrison, J.J., English, A.M., and Nguyen, D. 2013. The stringent response controls catalases in Pseudomonas aeruginosa and is required for hydrogen peroxide and antibiotic tolerance. J. Bacteriol. 195, 2011–2020.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kim, J.S., Cho, D.H., Heo, P., Jung, S.C., Park, M., Oh, E.J., Sung, J., Kim, P.J., Lee, S.C., Lee, D.H., et al. 2016. Fumarate-mediated persistence of Escherichia coli against antibiotics. Antimicrob. Agents Chemother. 60, 2232–2240.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kim, Y. and Wood, T.K. 2010. Toxins Hha and CspD and small RNA regulator Hfq are involved in persister cell formation through MqsR in Escherichia coli. Biochem. Biophys. Res. Commun. 391, 209–213.

    Article  CAS  PubMed  Google Scholar 

  • Kim, J.S., Yamasaki, R., Song, S., Zhang, W., and Wood, T.K. 2018. Single cell observations show persister cells wake based on ribosome content. Environ. Microbiol. 20, 2085–2098.

    Article  CAS  PubMed  Google Scholar 

  • Kohanski, M.A., DePristo, M.A., and Collins, J.J. 2010. Sublethal antibiotic treatment leads to multidrug resistance via radical-induced mutagenesis. Mol. Cell 37, 311–320.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Korch, S.B., Henderson, T.A., and Hill, T.M. 2003. Characterization of the hipA7 allele of Escherichia coli and evidence that high persistence is governed by (p)ppGpp synthesis. Mol. Microbiol. 50, 1199–1213.

    Article  CAS  PubMed  Google Scholar 

  • Kwan, B.W., Valenta, J.A., Benedik, M.J., and Wood, T.K. 2013. Arrested protein synthesis increases persister-like cell formation. Antimicrob. Agents Chemother. 57, 1468–1473.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kwon, O., Kotsakis, A., and Meganathan, R. 2000. Ubiquinone (coenzyme Q) biosynthesis in Escherichia coli: Identification of the ubiF gene. FEMS Microbiol. Lett. 186, 157–161.

    Article  CAS  PubMed  Google Scholar 

  • Lafleur, M.D., Qi, Q., and Lewis, K. 2010. Patients with long-term oral carriage harbor high-persister mutants of Candida albicans. Antimicrob. Agents Chemother. 54, 39–44.

    Article  CAS  Google Scholar 

  • Lebeaux, D., Ghigo, J.M., and Beloin, C. 2014. Biofilm-related infections: Bridging the gap between clinical management and fundamental aspects of recalcitrance toward antibiotics. Microbiol. Mol. Biol. Rev. 78, 510–543.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Leszczynska, D., Matuszewska, E., Kuczynska-Wisnik, D., Furmanek-Blaszk, B., and Laskowska, E. 2013. The formation of persister cells in stationary-phase cultures of Escherichia coli is associated with the aggregation of endogenous proteins. PLoS One 8, e54737.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Leung, V. and Levesque, C.M. 2012. A stress-inducible quorum-sensing peptide mediates the formation of persister cells with noninherited multidrug tolerance. J. Bacteriol. 194, 2265–2274.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Levin-Reisman, I., Ronin, I., Gefen, O., Braniss, I., Shoresh, N., and Balaban, N.Q. 2017. Antibiotic tolerance facilitates the evolution of resistance. Science 355, 826–830.

    Article  CAS  PubMed  Google Scholar 

  • Lewis, K. 2010. Persister cells. Annu. Rev. Microbiol. 64, 357–372.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Long, H., Miller, S.F., Strauss, C., Zhao, C., Cheng, L., Ye, Z., Griffin, K., Te, R., Lee, H., Chen, C.C., et al. 2016. Antibiotic treatment enhances the genome-wide mutation rate of target cells. Proc. Natl. Acad. Sci. USA 113, E2498–2505.

    Article  CAS  PubMed  Google Scholar 

  • Ma, C., Sim, S., Shi, W., Du, L., Xing, D., and Zhang, Y. 2010. Energy production genes sucB and ubiF are involved in persister survival and tolerance to multiple antibiotics and stresses in Escherichia coli. FEMS Microbiol. Lett. 303, 33–40.

    Article  CAS  PubMed  Google Scholar 

  • Maisonneuve, E., Castro-Camargo, M., and Gerdes, K. 2013. (p)ppGpp controls bacterial persistence by stochastic induction of toxin-antitoxin activity. Cell 154, 1140–1150.

    Article  CAS  PubMed  Google Scholar 

  • Moyed, H.S. and Bertrand, K.P. 1983. hipA, a newly recognized gene of Escherichia coli k-12 that affects frequency of persistence after inhibition of murein synthesis. J. Bacteriol. 155, 768–775.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Moyed, H.S. and Broderick, S.H. 1986. Molecular cloning and expression of hipA, a gene of Escherichia coli k-12 that affects frequency of persistence after inhibition of murein synthesis. J. Bacteriol. 166, 399–403.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mulcahy, L.R., Burns, J.L., Lory, S., and Lewis, K. 2010. Emergence of Pseudomonas aeruginosa strains producing high levels of persister cells in patients with cystic fibrosis. J. Bacteriol. 192, 6191–6199.

    Article  CAS  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., et al. 2011. Active starvation responses mediate antibiotic tolerance in biofilms and nutrient-limited bacteria. Science 334, 982–986.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Nierman, W.C., Yu, Y., and Losada, L. 2015. The in vitro antibiotic tolerant persister population in Burkholderia pseudomallei is altered by environmental factors. Front. Microbiol. 6, 1338.

    Article  PubMed  PubMed Central  Google Scholar 

  • Ron, E.Z. 2013. Bacterial stress response, pp. 589–603. In Rosenberg, E., DeLong, E.F., Lory, S., Stackebrandt, E., and Thompson, F. (eds.), The prokaryotes: Prokaryotic physiology and biochemistry, Springer Berlin Heidelberg, Berlin, Heidelberg, Germany.

    Chapter  Google Scholar 

  • Rotem, E., Loinger, A., Ronin, I., Levin-Reisman, I., Gabay, C., Shoresh, N., Biham, O., and Balaban, N.Q. 2010. Regulation of phenotypic variability by a threshold-based mechanism underlies bacterial persistence. Proc. Natl. Acad. Sci. USA 107, 12541–12546.

    Article  CAS  PubMed  Google Scholar 

  • Scherrer, R. and Moyed, H.S. 1988. Conditional impairment of cell division and altered lethality in hipA mutants of Escherichia coli K-12. J. Bacteriol. 170, 3321–3326.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Shah, D., Zhang, Z., Khodursky, A., Kaldalu, N., Kurg, K., and Lewis, K. 2006. Persisters: A distinct physiological state of E. coli. BMC Microbiol. 6, 53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Spoering, A.L. and Lewis, K. 2001. Biofilms and planktonic cells of Pseudomonas aeruginosa have similar resistance to killing by antimicrobials. J. Bacteriol. 183, 6746–6751.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Spoering, A.L., Vulic, M., and Lewis, K. 2006. GlpD and PlsB participate in persister cell formation in Escherichia coli. J. Bacteriol. 188, 5136–5144.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Srivatsan, A. and Wang, J.D. 2008. Control of bacterial transcription, translation and replication by (p)ppGpp. Curr. Opin. Microbiol. 11, 100–105.

    Article  CAS  PubMed  Google Scholar 

  • Van den Bergh, B., Fauvart, M., and Michiels, J. 2017. Formation, physiology, ecology, evolution and clinical importance of bacterial persisters. FEMS Microbiol. Rev. 41, 219–251.

    Article  CAS  PubMed  Google Scholar 

  • Vogel, J., Argaman, L., Wagner, E.G., and Altuvia, S. 2004. The small RNA IstR inhibits synthesis of an SOS-induced toxic peptide. Curr. Biol. 14, 2271–2276.

    Article  CAS  PubMed  Google Scholar 

  • Wen, Y., Behiels, E., and Devreese, B. 2014. Toxin-antitoxin systems: Their role in persistence, biofilm formation, and pathogenicity. Pathog. Dis. 70, 240–249.

    Article  CAS  PubMed  Google Scholar 

  • Windels, E.M., Michiels, J.E., Fauvart, M., Wenseleers, T., Van den Bergh, B., and Michiels, J. 2019. Bacterial persistence promotes the evolution of antibiotic resistance by increasing survival and mutation rates. ISME J. 13, 1239–1251.

    Article  CAS  PubMed  Google Scholar 

  • Wolfson, J.S., Hooper, D.C., McHugh, G.L., Bozza, M.A., and Swartz, M.N. 1990. Mutants of Escherichia coli K-12 exhibiting reduced killing by both quinolone and beta-lactam antimicrobial agents. Antimicrob. Agents Chemother. 34, 1938–1943.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wolfson, J.S., Hooper, D.C., Shih, D.J., McHugh, G.L., and Swartz, M.N. 1989. Isolation and characterization of an Escherichia coli strain exhibiting partial tolerance to quinolones. Antimicrob. Agents Chemother. 33, 705–709.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIT) (NRF-2019R1C1C1008856) and a grant from the BioNano Health-Guard Research Center funded by the Ministry of Science, ICT & Future Planning (MSIP) of Korea as a Global Frontier Project (2013M3A6B2078954), and by the KRIBB Initiative Research Program.

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  1. Infectious Disease Research Center, KRIBB, Daejeon, 34141, Republic of Korea

    Sung-Hee Jung, Choong-Min Ryu & Jun-Seob Kim

  2. Biosystems and Bioengineering Program, University of Science and Technology, Daejeon, 3414, Republic of Korea

    Sung-Hee Jung & Choong-Min Ryu

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  1. Sung-Hee Jung
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Correspondence to Jun-Seob Kim.

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Jung, SH., Ryu, CM. & Kim, JS. Bacterial persistence: Fundamentals and clinical importance. J Microbiol. 57, 829–835 (2019). https://doi.org/10.1007/s12275-019-9218-0

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