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Summary: Recurrent epidemics of drug-resistant Staphylococcus aureus illustrate the rapid lapse of antibiotic efficacy following clinical implementation. Over the last decade, community-associated methicillin-resistant S. aureus (MRSA) has emerged as a dominant cause of infections, and this problem is amplified by the hyper-virulent nature of these isolates. Herein, we report the discovery of a fungal metabolite, apicidin, as an innovative means to counter both resistance and virulence. Owing to its breadth and specificity as a quorum-sensing inhibitor, apicidin antagonizes all MRSA agr systems in a non-biocidal manner. In skin challenge experiments, the apicidin-mediated abatement of MRSA pathogenesis corresponds with quorum-sensing inhibition at in vivo sites of infection. Additionally, we show that apicidin attenuates MRSA-induced disease by potentiating innate effector responses, particularly through enhanced neutrophil accumulation and function at cutaneous challenge sites. Together, these results indicate that apicidin treatment represents a strategy to limit MRSA virulence and promote host defense. : Parlet et al. identified the apicidin family of fungal-derived compounds as potent inhibitors of Staphylococcus aureus agr quorum sensing. In a mouse model of skin infection, apicidin prevented agr activation and MRSA-induced dermonecrosis. Apicidin treatment also induced neutrophil accumulation and function at MRSA challenge sites, aiding host defense to infection. Keywords: Staphylococcus aureus, MRSA, quorum sensing, agr, apicidin, natural product, pathogenesis, skin infection