SpsB is a target of SOS-response inhibitor OXF-077 and regulates quinolone resistance emergence

Antimicrobial resistance (AMR) is a global health threat, urgently requiring novel compounds with new targets. One emerging strategy is the development of antibiotic adjuvants that inhibit the mutagenic SOS response in bacteria, thus prolonging antibiotic efficacy. OXF-077 is a potent SOS-response inhibitor that suppresses the emergence of ciprofloxacin resistance in Staphylococcus aureus; however, the cellular target of OXF-077 is unknown. We report here the use of affinity-based protein profiling to identify signal peptidase IB (SpsB) as a target of OXF-077. Genetic and chemical studies demonstrated that SpsB is required for the upregulation of the SOS response gene recA and increased frequency of resistance to ciprofloxacin. SpsB is therefore postulated to regulate the SOS response in S. aureus, representing a cell surface peptidase that can be targeted by small molecules to slow the evolution of resistance. Collectively, this work delivers SpsB as an attractive target to combat the urgent threat of AMR.