Abstract
Persisters constitute a population of temporarily antibiotic-tolerant variants in an isogenic bacterial population and are considered an important cause of relapsing infections. It is currently unclear how cellular damage inflicted by antibiotic action is reversed upon persister state exit and how this relates to antibiotic resistance development at the molecular level. We demonstrate that persisters, upon fluoroquinolone treatment, accumulate oxidative DNA damage, which is repaired through nucleotide excision repair. Detection of the damage occurs via transcription-coupled repair using UvrD-mediated backtracking or Mfd-controlled displacement of the RNA polymerase. This competition results in heterogeneity in persister awakening lags. Most persisters repair the oxidative DNA damage, displaying a mutation rate equal to the untreated population. However, the promutagenic factor Mfd increases the mutation rate in a persister subpopulation. Our data provide in-depth insight into the molecular mechanisms underlying persister survival and pinpoint Mfd as an important molecular factor linking persistence to resistance development.
Highlights
Every isogenic bacterial population harbors a subpopulation of non-growing antibiotic-tolerant cells that survive lethal drug exposure, named persisters
Absence of RecB, RecC, UvrA, UvrB, and UvrD impedes persister awakening after fluoroquinolone treatment To define which DNA repair pathways underlie persister cell survival after fluoroquinolone treatment, we hypothesized that the absence of a gene important for survival should result in a decreased persister fraction
The lower persister fraction of recB and recC mutants demonstrates the validity of our hypothesis, as RecB and RecC were recently linked with persister survival following their role in homologous recombination (HR) to repair the double-stranded breaks (DSBs) (Murawski and Brynildsen, 2021)
Summary
Every isogenic bacterial population harbors a subpopulation of non-growing antibiotic-tolerant cells that survive lethal drug exposure, named persisters. Evidence for the clinical importance of persister cells is accumulating, as they are held responsible for the recalcitrance of chronic infections (Lafleur et al, 2010; Fauvart et al, 2011; Schumacher et al, 2015; Fisher et al, 2017) and they constitute a pool from which resistant mutants emerge (Levin-Reisman et al, 2017; Sebastian et al, 2017; Windels et al, 2019; Liu et al, 2020). A positive correlation was found between the number of persisters in a bacterial population, and the emergence of resistant mutants in lab and natural E. coli strains (Windels et al, 2019). In this respect, the healthcare system would benefit from the development of anti-persister therapies
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