The antioxidant drug N-acetylcysteine abolishes SOS-mediated mutagenesis produced by fluoroquinolones in bacteria

Abstract

Certain antibiotics, particularly fluoroquinolones, induce the mutagenic SOS response and increase the levels of intracellular reactive oxygen species (ROS), which have been associated with antibiotic lethality. Both SOS and ROS promote bacterial mutagenesis, fueling the emergence of resistant mutants during antibiotic treatments. However, the relative contribution of ROS and SOS on this antibioticmediated mutagenesis is currently unknown. We used the antioxidant molecule N-acetylcysteine (NAC) to study the contribution of ROS on the SOS response and the mutagenesis mediated by the fluoroquinolone anti-biotic ciprofloxacin (CIP). We show that NAC is able to reduce intracellular ROS levels, as well as the SOS response caused by treatment with subinhibitory concentrations of CIP, without affecting its anti-bacterial activity. This effect reduces anti-bioticinduced mutagenesis to levels comparable to a translesion synthesis DNA-polymerases deficient strain, suggesting that ROS play a major role in SOS-induced mutagenesis. Collectively, our results shed light on the mechanisms underlying antibioticinduced mutagenesis and open the possibility for the use of NAC as adjuvant in antibiotic therapy to hinder the development of antibiotic resistance.