PLOS Genetics study maps epistasis between two DNA repair pathways in bacterial survival after antibiotic treatment

Researchers at Princeton University, led by Mark P. Brynildsen and colleagues, have published a study in PLOS Genetics investigating how two major DNA repair pathways — nucleotide excision repair (NER) and homologous recombination (HR) — interact epistatically to govern the recovery of bacterial persisters following fluoroquinolone (FQ) antibiotic treatment.

Persister cells are a sub-population of bacteria within a culture that survive antibiotic exposure not through acquired resistance mutations but through a transient, phenotypically tolerant state. Fluoroquinolones, which target DNA gyrase and topoisomerase IV to generate lethal double-strand DNA breaks, are among the most effective antibiotic classes against non-growing bacteria including those in stationary phase. Previous work established that FQ-treated persisters survive by actively repairing DNA damage rather than by avoiding it.

The new study dissects the genetic relationship between NER and HR in this repair process. Epistasis analysis — examining the phenotypic consequences of disrupting each pathway alone versus in combination — allows inference of whether the two pathways act in the same or parallel routes. The findings clarify the hierarchy and interdependence of these repair systems in post-FQ recovery, with implications for understanding why some persister populations are more refractory to treatment than others.

For researchers studying antibiotic tolerance and the roots of clinical treatment failure, the work provides a more granular picture of the repair genetics underpinning persistence. The study is peer-reviewed and published in full in PLOS Genetics.