Staphylococcus saprophyticus prevents skin damage by inhibiting Staphylococcus aureus quorum sensing

Coagulase-negative staphylococci are prominent skin commensals that play a crucial role in maintaining skin homeostasis and eliminating pathogens. Coagulase-negative staphylococci, such as Staphylococcus caprae, S. hominis, S. simulans, and S. warneri, have been implicated in suppressing skin inflammation by inhibiting S. aureus virulence; however, it remains unclear whether other staphylococcal species, including S. saprophyticus, also prevent S. aureus-induced skin injury. The present study showed that coagulase-negative S. saprophyticus suppresses skin damage by interfering with S. aureus accessory gene regulator (Agr) quorum sensing. To identify novel coagulase-negative staphylococci that inhibit S. aureus virulence, S. aureus was cultured in the presence of culture supernatants from various coagulase-negative Staphylococcus strains. S. saprophyticus culture supernatant significantly inhibited the virulence of S. aureus regulated by the Agr type-I and -II quorum sensing systems. S. saprophyticus secretes cognate autoinducing peptide (AIP) consisting of a 3-amino acid tail and a 5-amino acid thiolactone ring structure similar to that of S. aureus Agr type-I. Synthetic S. saprophyticus AIP mainly inhibited S. aureus Agr type-I and type-II signaling, without affecting pathogen growth. S. aureus Agr type-I virulence was partially inhibited by chimeric peptides in which either the tail or the thiolactone ring of S. aureus AIP was replaced with that of S. saprophyticus AIP. Furthermore, synthetic S. saprophyticus AIP significantly suppressed skin damage, which was associated with reduced pathogen loads, in murine epicutaneous and intradermal S. aureus inoculation models. Our findings demonstrate that commensal S. saprophyticus-derived AIP protects against cutaneous injury by interfering with S. aureus Agr quorum sensing.