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Proc Natl Acad Sci U S A. 2018 Jul 3;115(27):E6301-E6309. doi: 10.1073/pnas.1804218115. Epub 2018 Jun 18.

Timing of DNA damage responses impacts persistence to fluoroquinolones.

Author information

1
Department of Chemical and Biological Engineering, Princeton University, Princeton, NJ 08544.
2
Department of Chemical and Biological Engineering, Princeton University, Princeton, NJ 08544 mbrynild@princeton.edu.

Abstract

Bacterial persisters are subpopulations of phenotypic variants in isogenic cultures that can survive lethal doses of antibiotics. Their tolerances are often attributed to reduced activities of antibiotic targets, which limit corruption and damage in persisters compared with bacteria that die from treatment. However, that model does not hold for nongrowing populations treated with ofloxacin, a fluoroquinolone, where antibiotic-induced damage is comparable between cells that live and those that die. To understand how those persisters achieve this feat, we employed a genetic system that uses orthogonal control of MazF and MazE, a toxin and its cognate antitoxin, to generate model persisters that are uniformly tolerant to ofloxacin. Despite this complete tolerance, MazF model persisters required the same DNA repair machinery (RecA, RecB, and SOS induction) to survive ofloxacin treatment as their nongrowing, WT counterparts and exhibited similar indicators of DNA damage from treatment. Further investigation revealed that, following treatment, the timing of DNA repair was critical to MazF persister survival because, when repair was delayed until after growth and DNA synthesis resumed, survival was compromised. In addition, we found that, with nongrowing, WT planktonic and biofilm populations, stalling the resumption of growth and DNA synthesis after the conclusion of fluoroquinolone treatment with a prevalent type of stress at infection sites (nutrient limitation) led to near complete survival. These findings illustrate that the timing of events, such as DNA repair, following fluoroquinolone treatment is important to persister survival and provide further evidence that knowledge of the postantibiotic recovery period is critical to understanding persistence phenotypes.

KEYWORDS:

DNA damage; MazF; SOS response; persistence; starvation

PMID:
29915065
PMCID:
PMC6142227
DOI:
10.1073/pnas.1804218115
[Indexed for MEDLINE]
Free PMC Article

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