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Bacterial persistence: some new insights into an old phenomenon

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Abstract

Bigger discovered more than 60 years ago, at the very beginning of the antibiotic era, that populations of antibiotic-sensitive bacteria contained a very small fraction (approximately 10−6) of antibiotic-tolerant cells (persisters). Persisters are different from antibiotic-resistant mutants in that their antibiotic tolerance is non-heritable and reversible. In spite of its importance as an interesting biological phenomenon and in the treatment of infectious diseases, persistence did not attract the attention of the scientific community for more than four decades since its discovery. The main reason for this lack of interest was the difficulty in isolating sufficient numbers of persister cells for experimentation, since the proportion of persisters in a population of wild-type cells is extremely small. However, with the discovery of high-persister (hip) mutants of Escherichia coli by Moyed and his group in the early 1980s, the phenomenon attracted the attention of many groups and significant progress has occurred since then. It is now believed that persistence is the end result of a stochastic switch in the expression of some toxin-antitoxin (TA) modules (of which the hipA and hipB genes could be examples), creating an imbalance in their intracellular levels. There are also models invoking the involvement of the alarmone (p) ppGpp in the generation of persisters. However, the precise mechanisms are still unknown. Bacterial persistence is part of a wider gamut of phenomena variously called as bistability, multistability, phenotypic heterogeneity, stochastic switching processes, etc. It has attracted the attention of not only microbiologists but also a diverse band of researchers such as biofilm researchers, evolutionary biologists, sociobiologists, etc. In this article, I attempt to present a broad overview of bacterial persistence to illustrate its significance and the need for further exploration.

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Abbreviations

c-di-GMP:

(3′–5′) cyclic dimeric guanosine monophosphate

FMN:

flavin mononucleotide

GFP:

green fluorescent protein; glpD, glycerol-3-phosphate dehydrogenase

hip :

high-persister

MIC:

minimum inhibitory concentration

MRSA:

methicillinresistant Staphylococus aureus

ORF:

open reading frame

PCD:

programmed cell death

plsB :

glycerol-3-phosphate acyl transferase

(p)ppGpp:

gunanosine 3′ 5′ bispyrophosphate

TA:

toxin-antitoxin

References

  • Aizenman E, Engelberg-Kulka H and Glasser G 1996 An Escherichia coli “addiction module” regulated by guanosine 3′–5′-bispyrophosphate: a model for programmed cell death; Proc. Natl. Acad. Sci. USA 93 6059–6063

    Article  CAS  Google Scholar 

  • Anguera M C, Suh J R, Ghandour H, Nasreallah I M, Selhub J and Stover T J 2003 Methenyltetrahydrofolate synthetase regulates folate turn over and accumulation; J. Biol. Chem. 278 29856–29862

    Article  CAS  Google Scholar 

  • Aridesi J N, Zahller E, Roe F and Stewart P S 2003 Role of nutrient limitation and stationary phase existence in Klebsiella pneumoniae biofilm resistance to ampicillin and ciprofloxacin; Antimicrob. Agents Chemother. 47 1251–1256

    Article  Google Scholar 

  • Avery S V 2006 Microbial cell individuality and the underlying sources of heterogeneity; Nat. Rev. Microbiol. 4 577–587

    Article  CAS  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  Google Scholar 

  • Bigger J W 1944 Treatment of staphylococcal infections with penicillin; Lancet ii 497–500

    Article  Google Scholar 

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

    Article  CAS  Google Scholar 

  • Blaser M J and Kirscher D 2007 The equilibria that allow bacterial persistence in human hosts; Nature (London) 449 843–849

    Article  CAS  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  Google Scholar 

  • Christensen S K, Mikkelson M, Pedersen K and Gerdes K 2001 RelE, a global inhibitor of translation is activated during nutritional stress; Proc. Natl. Acad. Sci. USA 98 14328–14333

    Article  CAS  Google Scholar 

  • Christensen S K, Pedersen K, Hansen F G and Gerdes K 2003 Toxin-antitoxin loci as stress response elements: chpAK/mazF and chpB cleave translated RNAs and are counteracted by tmRNA; J. Mol. Biol. 332 809–819

    Article  CAS  Google Scholar 

  • Correia F F, I’Onofrio A, Rejter T, Li L, Karger B L, Makarova K, Koonin E V and Lewis K 2006 Kinase activity of over expressed HipA is required for growth arrest multidrug tolerance in Escherichia coli; J. Bacteriol. 188 8630–8637

    Article  Google Scholar 

  • Dodd I B, Sheerwin K E and Egan J B 2005 Revisited gene regulation in bacteriophage λ; Curr. Opin. Genet. Dev. 15 145–152

    Article  CAS  Google Scholar 

  • Dhar N and McKinney J D 2007 Microbial phenotypic heterogeneity and antibiotic tolerance; Curr. Opin. Microbiol. 10 30–38

    Article  CAS  Google Scholar 

  • Dubnau D and Losick R 2006 Bistability in bacteria; Mol. Microbiol. 61 564–572

    Article  CAS  Google Scholar 

  • Falla T J and Chopra I 1998 Joint tolerance to β-lactam and fluoroquinolone antibiotics in Escherichia coli results from over expression of hip A; Antimicrob. Agents Chemother. 42 3282–3284

    Article  CAS  Google Scholar 

  • Fux C A, Costerton J W, Stewart P S and Stoodley P 2005 Survival strategies in infectious biofilms; Trends Microbiol. 13 34–40

    Article  CAS  Google Scholar 

  • Gardner A, West S A and Giriffin A S 2007 Is bacterial persistence a social trait? PLoS ONE 2 e752

    Article  Google Scholar 

  • Gerdes K 2000 Toxin-antitoxin modules may regulate synthesis of macromolecules during nutritional stress; J. Bacteriol. 182 561–572

    Article  CAS  Google Scholar 

  • Gerdes K, Christensen S K and Lobner-Olessen A 2005 Prokaryotic toxin-antitoxin stress response loci; Nature Rev. Microbiol. 3 371–382

    Article  CAS  Google Scholar 

  • Gomez J E and McKinney J D 2004 M. tuberculosis persistence, latency and drug tolerance; Tuberculosis 84 29–44

    Article  Google Scholar 

  • Hall-Stoodley L, Costerton J W and Stoodley P 2004 Bacterial biofilms: From natural environment to infectious diseases; Nat. Rev. Microbiol. 2 95–108

    Article  CAS  Google Scholar 

  • Hansen S, Lewis K and Vulic M 2008 The role of global regulators and nucleotide metabolism in antibiotic tolerance in E. coli; Antimicrob. Agents Chemother. E-publication ahead of print, PMID: 18519731

  • 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  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  Google Scholar 

  • Hayes F 2003 Toxins-antitoxins: plasmid maintenance, programmed cell death and cell cycle arrest; Science 301 1496–1499

    Article  CAS  Google Scholar 

  • Hazen T, Sat B and Engelberg-Kulka H 2004 Escherichia coli mazEF-mediated cell death is triggerd by various stressful conditions; J. Bacteriol. 186 3663–3669

    Article  Google Scholar 

  • Jayaraman A and Wood T K 2008 Bacterial quorum sensing: signals, circuits, and implications for biofilms and disease; Annu. Rev. Biomed. Eng. 10 145–167

    Article  CAS  Google Scholar 

  • Jayaraman R 2000 Modulation of allele leakiness and adaptive mutability in Escherichia coli; J. Genet. 79 1–6

    Article  Google Scholar 

  • Kearns D B and Losick R 2005 Cell population heterogeneity during growth of Bacillus subtilis; Genes Dev. 19 3083–3094

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  • Kolter R and Greenberg E P 2006 The superficial life of microbes; Nature (London) 441 300–302

    Article  CAS  Google Scholar 

  • Korch S, Henderson T and Hill T 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  Google Scholar 

  • Korch S B and Hill T M 2006 Ectopic over expression of wild type and mutant hipA genes in Escherichia coli. Effects of macromolecular synthesis and persister formation; J. Bacteriol. 188 3826–3836

    Article  CAS  Google Scholar 

  • Kussell E, Kishony R, Balaban N Q and Leibler S 2005 Bacterial persistence: A model of survival in changing environments; Genetics 169 1807–1814

    Article  Google Scholar 

  • Kussell E and Leibler S 2005 Phenotypic diversity, population growth and information in fluctuating environments; Science 309 2075–2078

    Article  CAS  Google Scholar 

  • Kuznetsova E, Proudfoot M, Gonzalez CF, Brown G, Omelchenko M V, Borozan I, Carmel L, Wolf Y I, Mori H, Savchenko A V, Arrowsmith C H, Koonin E V, Edwards A N and Yakunin A F 2006 Genome-wide analysis of substrate specificities of the E. coli haloacid dehalogenase-like phosphatase family; J. Biochem. 281 36149–36161

    CAS  Google Scholar 

  • Lee S W, Foley E J and Epstein J A 1944 Mode of action of penicillin I. Bacterial growth and penicillin activity — Staphylococus aureus FDA; J. Bacteriol. 48 393–399

  • Levin B R 2004 Non-inherited resistance to antibiotics; Science 305 1578–1579

    Article  CAS  Google Scholar 

  • Levin B R and Rozen D E 2006 Noninherited antibiotic resistance; Nat. Rev. Microbiol. 4 556–562

    Article  CAS  Google Scholar 

  • Levy S B and Marshall B 2004 Antibacterial resistance worldwide: causes, challenges and responses; Nature Med. 10 S122–S129

    Article  CAS  Google Scholar 

  • Lewis K 2000 Programmed cell death in bacteria; Microbiol. Mol. Biol. Rev. 64 503–514

    Article  CAS  Google Scholar 

  • Lewis K 2001 Riddle of biofilms resistance; Antimicrob. Agents Chemother. 45 999–100

    Article  CAS  Google Scholar 

  • Lewis K 2005 Persister cells and the riddle of biofilm survival; Biochemistry (Moscow) 70 267–274

    Article  CAS  Google Scholar 

  • Lewis K 2007 Persister cells, dormancy and infectious disease; Nat. Rev. Microbiol. 5 48–56

    Article  CAS  Google Scholar 

  • Lewis K 2008 Multidrug tolerance of biofilms and persister cells; Curr. Top. Microbiol. Immunol. 322 107–132

    CAS  PubMed  Google Scholar 

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

    Article  CAS  Google Scholar 

  • Maamar H and Dubnau D 2005 Bistability in the Bacillus subtilis K-state (competence) system requires a positive feedback; Mol. Microbiol. 56 615–624

    Article  CAS  Google Scholar 

  • McCune R M Jr and Tompsett R 1956 Fate of Mycobacterium tuberculosis in mouse tissues as determined by the microbial enumeration technique I. Persistence of drug susceptible bacilli in the tissues despite prolonged antimicrobial therapy; J. Exp. Med. 104 737–763

    Article  CAS  Google Scholar 

  • McDermott W 1958 Microbial persistence; Yale J. Biol. Med. 30 257–291

    CAS  PubMed  Google Scholar 

  • Miller C, Thomsen L E, Gaggero C, Mosseri R, Ingmar H and Cohen S N 2004 SOS response induction by β-lactams and bacterial defence against antibiotic lethality; Science 305 1629–1631

    Article  CAS  Google Scholar 

  • Moyed H S and Bertrand K P 1983 hipA, a newly recognized gene of Escherichia coli K12 that affects the frequency of persisters 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 K12 that affects the frequency of persistence after inhibition of murein synthesis; J. Bacteriol. 166 399–403

    Article  CAS  Google Scholar 

  • Parsek M R and Greenberg E P 2005 Sociomicrobiology: The connection between quorum sensing and biofilms; Trends Microbiol. 13 27–33

    Article  CAS  Google Scholar 

  • Pedersen K, Christensen S K and Gerdes K 2002 Rapid induction and reversal of a bacteriostatic condition controlled by the expression of toxins and anti-toxins. Mol. Microbiol. 45 501–510

    Article  CAS  Google Scholar 

  • Ptashne M 2004 A genetic switch: Phage λ revisited. 3rd edition. (New York: Cold Spring Harbor)

    Google Scholar 

  • Rodionov D G and Ishiguro E E 1995 Direct correlation between overproduction of guanosine 3′-5′-bisphyrophosphate (ppGpp) and penicillin tolerance in Escherichia coli; J. Bacteriol. 177 4224–4229

    Article  CAS  Google Scholar 

  • Sat B, Hazan T, Khaner H and Engelberg-Kulka H 2001 Programmed cell death in Escherichia coli: some antibiotics trigger maz EF lethality; J. Bacteriol. 183 2041–2045

    Article  CAS  Google Scholar 

  • Schreiber G S Metzger S, Aizenman E, Roza S, Cashel M and Glaser G 1991 Overexpression of the relA gene in Escherichia coli; J. Biol. Chem. 266 3760–3767

    CAS  PubMed  Google Scholar 

  • Shah D, Zhang Z, Kodursky A, Kaldalu N, Kurg K and Lewis K 2006 Persisters: a distinct physiological state of E. coli; BMC Microbiol. 6 e53

    Article  Google Scholar 

  • Singh E K, Utaida S, Jackson L S, Jayaswal R K, Wilkinson D J and Chamberlain N R 2007 Role for dnaK locus in tolerance of multiple stresses in Staphylococcus aureus; Microbiology 153 162–3173

    Article  Google Scholar 

  • Smits W K, Kuiper O P and Veening J W 2006 Phenotypic variation in bacteria: role of feedback regulation; Nat. Rev. Microbiol. 4 259–271

    Article  CAS  Google Scholar 

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

    Article  CAS  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 3494–3497

    Article  Google Scholar 

  • Suel G M, Garcia-Ojalvo J, Lieberman L M and Elowitz M B 2006 An excitable gene regulatory circuit induces transient cellular differentiation; Nature (London) 440 545–550

    Article  Google Scholar 

  • Trumanen E, Cozens R, Tosch W, Zak O and Tomasz A 1986 The rate of killing of E. coli by β-lactam antibiotics is strictly proportional to the bacterial growth; J. Gen. Microbiol. 132 1297–1304

    Google Scholar 

  • Van Sinderen D, Luttinger A, Kong L, Dubnau D, Venema G and Hamoen L 1995 ComK encodes the competence transcription factor, the key regulating protein for competence development in Bacillus subtilis; Mol. Microbiol. 15 455–462

    Article  Google Scholar 

  • Vazquez-Laslop N, Lee H and Neyfakh A A 2006 Increased persistence in Escherichia coli caused by controlled expression of toxins or other unrelated proteins; J. Bacteriol. 188 3494–3497

    Article  CAS  Google Scholar 

  • West S A, Griffin A S, Gardner A and Diggle S P 2006 Social evolution theory for microorganisms; Nat. Rev. Microbiol. 4 597–607

    Article  CAS  Google Scholar 

  • West S A, Diggle S P, Buckling A, Gardner A and Griffin A S 2007a The social lives of microbes; Annu. Rev. Ecol. Evol. Syst. 38 53–77

    Article  Google Scholar 

  • West S A, Griffin A S and Gardner A 2007b Social semantics: Altruism, Cooperation, Mutualism, Strong reciprocity and Group selection; J. Evol. Biol. 20 415–432

    Article  CAS  Google Scholar 

  • Wiuff C, Zappala R M, Regoes R R, Garner K N, Baquero F and Levin B R 2005 Phenotypic tolerance: Antibiotic enrichment of non-inherited resistance in bacterial populations; Antimicrob. Agents Chemother. 49 1483–149

    Article  CAS  Google Scholar 

  • Wolfson J S, Hooper D C, McHugh G L, Bozza M A and Swartz M N 1990 Mutants of Escherichia coli K12 exhibiting reduced killing by both quinolone and beta-lactam antimicrobial agents; Antimicrob. Agents Chemother. 34 1938–1943

    Article  CAS  Google Scholar 

  • Zeller H J and Voigt W H 1987 Efficacy of ciprofloxacin in stationary phase bacteria in vitro; Am. J. Med. 82 87–90

    Google Scholar 

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  1. Department of Molecular Biology, School of Biological Sciences, Madurai Kamaraj University, Madurai, 625 021, India

    R. Jayaraman

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Jayaraman, R. Bacterial persistence: some new insights into an old phenomenon. J. Biosci. 33, 795–805 (2008). https://doi.org/10.1007/s12038-008-0099-3

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