Signaling-mediated bacterial persister formation

Vega, Nicole M.; Allison, Kyle R; Khalil, Ahmad S.; Collins, James J.

doi:10.1038/nchembio.915

Cited by 364 publications

(413 citation statements)

References 25 publications

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“…3d). Factors such as quorum sensing, cell density, nutrient starvation, diauxic carbon source transitions, environmental signals (such as heat shock, oxidative stress and DNA damage) and stringent response pathways contribute to microbial persistence in vitro [54][55][56][57][58][59] . TA modules that are upregulated in persisters are terminal effectors of microbial persistence 60,61 .…”

Section: Discussionmentioning

confidence: 99%

MazF ribonucleases promote Mycobacterium tuberculosis drug tolerance and virulence in guinea pigs

et al. 2015

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Toxin-antitoxin (TA) systems are highly conserved in members of the Mycobacterium tuberculosis (Mtb) complex and have been proposed to play an important role in physiology and virulence. Nine of these TA systems belong to the mazEF family, encoding the intracellular MazF toxin and its antitoxin, MazE. By overexpressing each of the nine putative MazF homologues in Mycobacterium bovis BCG, here we show that Rv1102c (MazF3), Rv1991c (MazF6) and Rv2801c (MazF9) induce bacteriostasis. The construction of various single-, double-and triple-mutant Mtb strains reveals that these MazF ribonucleases contribute synergistically to the ability of Mtb to adapt to conditions such as oxidative stress, nutrient depletion and drug exposure. Moreover, guinea pigs infected with the triple-mutant strain exhibits significantly reduced bacterial loads and pathological damage in infected tissues in comparison with parental strain-infected guinea pigs. The present study highlights the importance of MazF ribonucleases in Mtb stress adaptation, drug tolerance and virulence.

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Section: Discussionmentioning

confidence: 99%

MazF ribonucleases promote Mycobacterium tuberculosis drug tolerance and virulence in guinea pigs

et al. 2015

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“…63 This appears to be dependent on activation of the OxyR-and phage shock pathways. By contrast, TA-associated persister formation has, in most publications, suggested to be stochastic, i.e., generating some cells in which growth is arrested.…”

Section: Acknowledgmentsmentioning

confidence: 99%

The toxin-antitoxin systemtisB-istR1

Wagner

Unoson

2012

RNA Biology

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“…25,26 However, their strategy is only effective for aminoglycoside antibiotics, and the sugar concentrations required to evoke a response in persisters are in millimolar range. Our strategy to inhibit HipA toxin is independent of the antibiotic types, which is more generally applicable.…”

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confidence: 99%

Novel Inhibitors of Toxin HipA Reduce Multidrug Tolerant Persisters

Yin

Liu

et al. 2016

ACS Med. Chem. Lett.

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Persisters are a small fraction of drug-tolerant bacteria without any genotype variations. Their existence in many life-threatening infectious diseases presents a major challenge to antibiotic therapy. Persistence is highly related to toxin−antitoxin modules. HipA (high persistence A) was the first toxin found to contribute to Escherichia coli persistence. In this study, we used structure-based virtual screening for HipA inhibitors discovery and identified several novel inhibitors of HipA that remarkably reduced E. coli persistence. The most potent one decreased the persister fraction by more than five-fold with an in vitro K D of 270 ± 90 nM and an ex vivo EC 50 of 46 ± 2 and 28 ± 1 μM for ampicillin and kanamycin screening, respectively. These findings demonstrated that inhibition of toxin can reduce bacterial persistence independent of the antibiotics used and provided a framework for persistence treatment by interfering with the toxin−antitoxin modules.

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Signaling-mediated bacterial persister formation

Cited by 364 publications

References 25 publications

MazF ribonucleases promote Mycobacterium tuberculosis drug tolerance and virulence in guinea pigs

MazF ribonucleases promote Mycobacterium tuberculosis drug tolerance and virulence in guinea pigs

The toxin-antitoxin systemtisB-istR1

Novel Inhibitors of Toxin HipA Reduce Multidrug Tolerant Persisters

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