Role of Global Regulators and Nucleotide Metabolism in Antibiotic Tolerance in
            <i>Escherichia coli</i>

Hansen, Sonja; Lewis, Kim; Vulić, Marin

doi:10.1128/aac.00144-08

Cited by 277 publications

(269 citation statements)

References 68 publications

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“…Among these genes are those that encode transcriptional regulators (ebgR, cspA, and yeeY), which is consistent with the results of a previous largescale screen for persister alleles (32). We identified three alleles previously associated with drug tolerance: disruption of mdtJ reduced persistence of the hipA7 strain presumably because this gene is involved in multidrug export (33); disruption of gadX, which is involved with multidrug resistance (34), increased the persistence rate of the metG2 strain; and we observed reduced persistence of hipA7 by deleting cspA, whose expression has been shown to be induced by antibiotic treatment (35).…”

Section: Characterization Of Persistence Through Genetic Interaction supporting

confidence: 88%

Large mutational target size for rapid emergence of bacterial persistence

Girgis

Harris²,

Tavazoie³

2012

Proc. Natl. Acad. Sci. U.S.A.

113

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Phenotypic heterogeneity displayed by a clonal bacterial population permits a small fraction of cells to survive prolonged exposure to antibiotics. Although first described over 60 y ago, the molecular mechanisms underlying this behavior, termed persistence, remain largely unknown. To systematically explore the genetic basis of persistence, we selected a library of transposon-mutagenized Escherichia coli cells for survival to multiple rounds of lethal ampicillin exposure. Application of microarray-based genetic footprinting revealed a large number of loci that drastically elevate persistence frequency through null mutations and domain disruptions. In one case, the C-terminal disruption of methionyl-tRNA synthetase (MetG) results in a 10,000-fold higher persistence frequency than wild type. We discovered a mechanism by which null mutations in transketolase A ( tktA ) and glycerol-3-phosphate (G3P) dehydrogenase ( glpD ) increase persistence through metabolic flux alterations that increase intracellular levels of the growth-inhibitory metabolite methylglyoxal. Systematic double-mutant analyses revealed the genetic network context in which such persistent mutants function. Our findings reveal a large mutational target size for increasing persistence frequency, which has fundamental implications for the emergence of antibiotic tolerance in the clinical setting.

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Section: Characterization Of Persistence Through Genetic Interaction supporting

confidence: 88%

Large mutational target size for rapid emergence of bacterial persistence

Girgis

Harris²,

Tavazoie³

2012

Proc. Natl. Acad. Sci. U.S.A.

113

View full text Add to dashboard Cite

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“…For example, both in E. coli and in P. aeruginosa, these include dksA, relA and spoT, genes associated with the stringent response (Hansen et al, 2008;Korch et al, 2003;Viducic et al, 2006). However, because of their simultaneous involvement in additional processes, their suitability as candidate drug targets remains to be determined.…”

Section: Global Regulatorsmentioning

confidence: 99%

Role of persister cells in chronic infections: clinical relevance and perspectives on anti-persister therapies

Fauvart

Groote

Michiels

2011

Journal of Medical Microbiology

369

319

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“…A B C D with the fact that it has been hard to demonstrate that deletion of this module significantly changes persister fraction (16). Under either assumption, we can explain the much smaller persister fraction observed in the wild-type strain.…”

Section: Resultsmentioning

confidence: 81%

Growth feedback as a basis for persister bistability

Feng

Kessler

Ben‐Jacob

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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A small fraction of cells in many bacterial populations, called persisters, are much less sensitive to antibiotic treatment than the majority. Persisters are in a dormant metabolic state, even while remaining genetically identical to the actively growing cells. Toxin and antitoxin modules in bacteria are believed to be one possible cause of persistence. A two-gene operon, HipBA, is one of many chromosomally encoded toxin and antitoxin modules in Escherichia coli and the HipA7 allelic variant was the first validated high-persistence mutant. Here, we present a stochastic model that can generate bistability of the HipBA system, via the reciprocal coupling of free HipA to the cellular growth rate. The actively growing state and the dormant state each correspond to a stable state of this model. Fluctuations enable transitions from one to the other. This model is fully in agreement with experimental data obtained with synthetic promoter constructs.A s far back as the 1940s, it was known that a small fraction of a bacterial population can survive even when exposed to prolonged antibiotic treatment (1, 2). This phenomenon is termed persistence and members of the surviving subpopulation are called persisters. It has been estimated that the frequency of persisters in normal wild-type populations is extremely small, perhaps of order 10 −5 ∽10 −6 (3). Although the number of persisters is tiny, they are often the main obstacle to attempts to completely eradicate infection.Remarkably, there is no apparent change in the persisters' DNA sequence; i.e., their survival is not due to mutation (4). Already in 1944, Bigger suggested that persisters are phenotypically different, in a dormant state instead of an actively growing state (1). The dormant state is presumably better able to deal with common antibiotics, which typically target only actively growing cells. Bigger's assumption was confirmed by a later study (3). In this study, Balaban et al. investigated the persistence of a single cell of Escherichia coli by using a microfluidic device. They showed that individual persisters do not always remain in the dormant state. Instead, they stochastically transit into an actively growing state and these newly transited cells are indistinguishable from other normally growing cells. Conversely, normal cells can transit into the persistent state. Thus, bacterial persistence at the population level is governed by a single-cell "phenotypic switch." The precise workings of this switch have to date remained unclear.In the 1980s, Moyed and Bertrand identified the first highpersistence mutant, HipA7, having a persister frequency that is near 10 −2 (4). The discovery of HipA7 facilitated the study of bacterial persistence due to its relatively high proportion of persisters. It was found that HipA7 is formed by a two-residue substitution in the HipA protein. This protein acts as a toxin in a toxin-antitoxin (TA) module (5, 6), where the hipB gene is coexpressed with hipA and the corresponding protein binds to and neutralizes HipA toxicity. To da...

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Role of Global Regulators and Nucleotide Metabolism in Antibiotic Tolerance in Escherichia coli

Cited by 277 publications

References 68 publications

Large mutational target size for rapid emergence of bacterial persistence

Large mutational target size for rapid emergence of bacterial persistence

Role of persister cells in chronic infections: clinical relevance and perspectives on anti-persister therapies

Growth feedback as a basis for persister bistability

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