Apicidin mediated attenuation of MRSA virulence corresponds with quorum sensing inhibition and enhanced immune effector responses.

Abstract

Abstract As the leading cause of infectious mortality in the United States, S. aureus-induced disease represents a major healthcare problem. The alarming rise of infections caused by virulent, antibiotic resistant strains, such as emerging methicillin-resistant S. aureus (MRSA) isolates, highlight the need for new interventions that inhibit MRSA pathogenicity and potentiate host defense responses. The expression of MRSA virulence factors is a function of agr-driven quorum sensing, making this system a promising target for anti-MRSA therapies. Through agr-reporter-based screens, a class of compounds, called apicidins, were found to inhibit quorum-sensing activity across MRSA isolates. To test the efficacy of apicidin in vivo, mice were challenged intradermally with 2×107 MRSA (+/−) 5 mg apicidin. The abatement MRSA virulence in the apicidin-treated group was demonstrated by reduced: weight loss, dermonecrosis and cutaneous bacterial burden. By challenging mice with an agr-reporter strain, we also found that the apicidin-mediated attenuation of MRSA pathogenesis corresponded with reduced quorum sensing activity in vivo. To evaluate apicidin’s impact upon anti-MRSA effector responses, we assessed polymorphonuclear neutrophil (PMN) accumulation and function at cutaneous sites of infection. Flow cytometric analysis revealed that apicidin increased the density of PMNs within infected wounds 24 hours post infection. In addition, we found that the number of PMNs that phagocytosed MRSA organisms in vivo was increased in lesional skin preparations from apicidin treated mice. Together, these results indicate that apicidin-mediated quorum quenching represents a novel strategy to limit MRSA virulence and promote host defense.