Received for publication December 10, 2007.
Revised February 26, 2008.
Accepted for publication February 26, 2008.

Discovery of a quorum sensing inhibitor of drug resistant staphylococcal infections by structure-based virtual screening

Abstract

Staphylococci are a major health threat due to increasing resistance to antibiotics. An alternative to antibiotic treatment is preventing virulence by inhibition of bacterial cell-to-cell communication using the quorum sensing inhibitor RNAIII-inhibiting peptide (RIP). In this work we identified hamamelitannin as a nonpeptide analog of RIP by virtual screening of a RIP-based pharmacophore against a database of commercially available small-molecule compounds. Hamamelitannin is a natural product found in the bark of witch hazel, has no effect on staphylococcal growth in vitro, but like RIP, it does inhibit the quorum-sensing regulator RNAIII. In a rat graft model hamamelitannin prevented device-associated infections in vivo, including infections caused by methicillin resistant S. aureus and S. epidermidis (MRSA, MRSE) strains . These findings suggest that hamamelitannin may be used as a suppressor to staphylococcal infections.

Key words: Structure-activity relationships and modeling, Protein targets, Antibiotic resistance