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.

Summary: Wooden boards were obtained from 3 cheese-processing facilities and assessed for bacterial diversity. Samples were obtained from the surface and at depths of 0.2 and 0.9 cm. DNA was extracted and amplified by PCR and 16S rRNA analysis was performed to identify bacterial communities present on the surface and within the boards. Although there was board-to-board variation in both diversity and richness, all boards contained bacteria in the phyla Actinobacteria, Firmicutes, and Proteobacteria. In general, the boards selected for saltand cold-tolerant bacteria, with 7 operational taxonomic units (Staphylococcus, Brevibacterium, Psychrobacter, Brachybacterium, Jeotgalicoccus, Nocardiopsaceae, and Yaniella) forming a core microbiota found on all boards.