Chemical proteomics identifies signal peptidase IB (SpsB) as a target of the SOS response inhibitor OXF-077 and a regulator of quinolone resistance emergence in Staphylococcus aureus

Antimicrobial resistance (AMR) is an existential threat to health globally, and novel compounds that act through new targets are urgently required to combat increasing levels of resistance. One emerging strategy is the development of ‘antibiotic adjuvants’ that can slow the evolution of resistance by inhibiting the mutagenic SOS response in bacteria, in order to prolong the clinical lifetime of antibiotics. 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 upregulation of the SOS response gene recA , increased frequency of resistance emergence to ciprofloxacin, and activation of the mutagenic SOS response in S. aureus . SpsB is therefore postulated to regulate the quinolone-activated SOS response in S. aureus , and can be targeted by small-molecule inhibitors such as OXF-077 to slow the evolution of resistance. Collectively, this work delivers SpsB as an attractive new drug target for the development of antibiotic adjuvants to combat the urgent threat of AMR.