A synthetic peptide was found to block cell-to-cell signalling, or quorum sensing, in bacteria and be highly bioavailable in mouse tissue. The controlled release of this agent from degradable polymeric microparticles strongly inhibited skin infection in a wound model at levels that far surpassed the potency of the peptide when delivered conventionally.
There is significant interest in approaches to the treatment of bacterial infections that block virulence without creating selective pressures that lead to resistance. Here, we report the development of an “anti-virulence” strategy that exploits the activity of potent synthetic inhibitors of quorum sensing (QS) in Staphylococcus aureus. We identify peptide-based inhibitors of QS that are resistant to sequestration or degradation by components of murine tissue and demonstrate that encapsulation of a lead inhibitor in degradable polymer microparticles provides materials that substantially inhibit QS in vitro. Using a murine abscess model, we show that this inhibitor attenuates methicillin-resistant S. aureus (MRSA) skin infections in vivo, and that sustained release of the inhibitor from microparticles significantly improved outcomes compared to mice that received a single-dose bolus. Our results present an effective and modular approach to controlling bacterial virulence in vivo and could advance the development of new strategies for skin infection control.
Keywords: Anti-Infective; Cell-Cell Signalling; Controlled Release; Peptides; Quorum Sensing.
© 2022 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH.