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

Madanahally D Kiran, Nallini Vijayarangan Adikesavan, Oscar Cirioni, Andrea Giacometti, Carmela Silvestri, Giorgio Scalise, Roberto Ghiselli, Vittorio Saba, Fiorenza Orlando, Menachem Shoham, Naomi Balaban

Index: Mol. Pharmacol. 73(5) , 1578-86, (2008)

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Abstract

Staphylococci are a major health threat because of 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 2',5-di-O-galloyl-d-hamamelose (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 Hamamelis virginiana (witch hazel), and it 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 Staphylococcus aureus and Staphylococcus epidermidis strains. These findings suggest that hamamelitannin may be used as a suppressor to staphylococcal infections.