Tolerance of Escherichia coli to fluoroquinolone antibiotics depends on specific components of the SOS response pathway.
Bacteria exposed to bactericidal fluoroquinolone (FQ) antibiotics can survive without becoming genetically resistant. Survival of these phenotypically resistant cells, commonly called "persisters," depends on the SOS gene network. We have examined mutants in all known SOS-regulated genes to identify functions essential for tolerance in Escherichia coli. The absence of DinG and UvrD helicases and the Holliday junction processing enzymes RuvA and RuvB leads to a decrease in survival. Analysis of the respective mutants indicates that, in addition to repair of double-strand breaks, tolerance depends on the repair of collapsed replication forks and stalled transcription complexes. Mutation in recF results in increased survival, which identifies RecAF recombination as a poisoning mechanism not previously linked to FQ lethality. DinG acts upstream of SOS promoting its induction, whereas RuvAB participates in repair only. UvrD directly promotes all repair processes initiated by FQ-induced damage and prevents RecAF-dependent misrepair, making it one of the crucial SOS functions required for tolerance.
Antimicrobial Discovery Center, Department of Biology, Northeastern University, Boston, Massachusetts 02115.
Alyssa
A
Theodore
Kim
K
Lewis
Marin
M
Vulic
D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D053903:DNA Breaks, Double-Stranded; D004265:DNA Helicases / Q000235:genetics / Q000378:metabolism; D024881:Drug Resistance, Bacterial / Q000235:genetics*; D004926:Escherichia coli / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism; D029968:Escherichia coli Proteins / Q000235:genetics / Q000378:metabolism; D024841:Fluoroquinolones / Q000494:pharmacology*; D019384:Nucleic Acid Synthesis Inhibitors / Q000494:pharmacology*; D013014:SOS Response, Genetics
D000900:Anti-Bacterial Agents; D029968:Escherichia coli Proteins; D024841:Fluoroquinolones; D019384:Nucleic Acid Synthesis Inhibitors; C074432:dinG protein, E coli; C071059:Holliday junction DNA helicase, E coli; C506746:UvrD protein, E coli; D004265:DNA Helicases
DNA repair; SOS response; fluoroquinolones; persisters; tolerance