The antioxidant drug Nacetylcysteine abolishes SOS mediated mutagenesis produced by fluoroquinolones in bacteria

• Published in: bioRxiv
• Main Authors: Rodriguez- Rosado, Ana, Valencia, Estela Ynes, Rodriguez- Rojas, Alexandro, Coloma Costas- Romero, Galhardo, Rodrigo S, Jesus Blazquez Gomez, Rodriguez- Beltran, Jeronimo
• Format: Paper
• Language: English
• Published: Cold Spring Harbor Cold Spring Harbor Laboratory Press 09.10.2018
• Subjects: Acetylcysteine; Antibacterial activity; Antibiotic resistance; Antibiotics; Antimicrobial resistance; Antioxidants; Bacteria; Ciprofloxacin; DNA biosynthesis; DNA-directed DNA polymerase; Fluoroquinolones; Intracellular; Lethality; Mutagenesis; Reactive oxygen species; Resistant mutant; SOS response
• DOI: 10.1101/428961

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 antibiotic mediated 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 antibiotic 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 antibacterial activity. This effect reduces antibioticinduced 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. Importance: The development of antimicrobial resistance, together with the existing paucity in the antibiotic pipeline, renders every antibiotic into a nonrenewable resource that should be carefully rationed. This worrisome scenario is exacerbated by the fact that treatment with certain antibiotics, besides killing bacteria, increase the chances of surviving bacteria to acquire resistance as a sideeffect. The mechanisms underlying this phenomenon involve complex bacterial physiological responses to antibiotics such as induction of the SOS response and the generation of reactive oxygen species. In this work, we demonstrate that the antioxidant drug Nacetylcysteine inhibits antibioticinduced mutagenesis by reducing the levels of reactive oxygen species and SOS induction in bacterial cells upon antibiotic treatment. Our results strongly suggest that reactive oxygen species are a key factor in antibiotic induced SOS mutagenesis and open the possibility of using NAC combined with antibiotic therapy to counteract the development of antibiotic resistance.