525 Novel peptide from commensal Staphylococcus simulans blocks MRSA quorum sensing and protects host skin from damage

Abstract

The human skin is colonized by a diverse array of bacteria, archaea, fungi, and viruses. Recent studies highlight the abundance of commensal coagulase-negative staphylococci (CoNS) as well as the relative absence of methicillin resistant Staphylococcus aureus (MRSA) on healthy skin. A widely recognized mechanism of bacterial competition is the quorum sensing Accessory Gene Regulator (agr) system, ubiquitous among staphylococci. We hypothesize that agr signaling facilitates interspecies cross-talk between CoNS and MRSA, resulting in a colonization advantage for CoNS and protecting the host from MRSA colonization or infection. A screen of CoNS spent media with potential inhibitory activity against MRSA agrsignaling identified Staphylococcus simulans as an attractive candidate to explore this hypothesis. S. simulans is a rare CoNS commensal of human skin, and we found that S. simulans spent media was sufficient to inhibit MRSA agr signaling in vitro. Mass spectrometry analysis of spent media revealed a unique 9 amino acid AIP and an MS confirmed AIP matching the native structure was synthesized for further analysis. The synthetic AIP inhibited MRSA agr signaling in vitro with nanomolar potency. Addition of synthetic AIP reduced MRSA skin damage in a murine model of infection. Finally, mice co-challenged with S. simulans and MRSA were significantly more protected from dermonecrosis than MRSA single challenge. Co-challenged mice also showed accelerated MRSA clearance compared to single challenge. These results suggest that cross-talk between CoNS and MRSA may be important in maintaining healthy skin homeostasis and preventing MRSA skin damage. Current investigations include the characterization of inhibitory AIPs produced by frequently isolated CoNS like Staphylococcus hominis. In vitro and ex vivo models of human skin that better match the native environment are also in development to assess CoNS-MRSA interactions.