RexAB is essential for the mutagenic repair of Staphylococcus aureus DNA damage caused by co-trimoxazole

Abstract

Co-trimoxazole (SXT) is a combination therapeutic that consists of sulfamethoxazole and trimethoprim that is increasingly used to treat skin and soft-tissue infections caused by methicillin-resistant Staphylococcus aureus (MRSA). However, the use of SXT is limited to the treatment of low-burden, superficial S. aureus infections and its therapeutic value is compromised by the frequent emergence of resistance. As a first step towards the identification of approaches to enhance the efficacy of SXT, we examined the role of bacterial DNA repair in antibiotic susceptibility and mutagenesis. This revealed that SXT caused DNA damage in S. aureus via both thymidine limitation and the generation of reactive oxygen species. Then, using mutants defective for DNA repair, it was found that repair of this damage required the RexAB nuclease/helicase complex, indicating that SXT causes DNA double-strand breaks. Furthermore, RexAB-mediated DNA repair led to induction of the SOS response, which resulted in an increased mutation rate and may explain the frequent emergence of resistant strains during SXT therapy. In summary, this work determined that SXT causes DNA damage in S. aureus via both thymidine limitation and oxidative stress, which is repaired by the RexAB complex, leading to induction of the mutagenic SOS response. Small molecule inhibitors of RexAB could therefore have therapeutic value by increasing the efficacy of SXT and decreasing the emergence of drug-resistance during treatment of infections caused by S. aureus.