Abstract: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 micro particles 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 micro particles significantly improved outcomes comparedt o 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.
Introduction
Hospital-acquired infections present a sustained and increasingly critical health threat. Staphylococcusaureus, an opportunistic Gram-positive pathogen, currently causes over 100000 hospital-acquired infections per year in the US alone, withn early 20 000 of those infections becoming fatal.[1] A major barrier to combating S. aureus infections is the emergence of wide spread resistance to conventional antibiotics, with strains such as the persistent methicillin-resistant S. aureus(MRSA) plaguing health care systems worldwide.[2] This emerging antibiotic crisis has motivated researchers to explore alternative, non-biocidal approaches to treat and clear bacterial infections. So-called “anti-virulence” strategies are of particular interestin this context, as the yaim to reduce the severity of an infection without killing the infective organism. By doing so, they reduce selective pressures that ultimately lead to resistance and potentially allow a host’s immune response to naturally clear the infection…..
