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First published on February 26, 2008; DOI: 10.1124/mol.107.044164

0026-895X/08/7305-1578-1586$20.00
Mol Pharmacol 73:1578-1586, 2008

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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, and Naomi Balaban

Department of Biomedical Sciences, Cummings School of Veterinary Medicine, Tufts University, North Grafton, Massachusetts (M.D.K., N.B.); Department of Biochemistry, Case Western Reserve University, Cleveland, Ohio (N.V.A., M.S.); Institute of Infectious Diseases and Public Health, University of Ancona, Ancona, Italy (O.C., A.G., C.S., G.S.); Department of General Surgery, Instituto Nazionale Riposo e Cura Anziani/Instituto de Ricovero e Cura a Carattere Scientifico (INRCA IRRCS), University of Ancona, Ancona, Italy (R.G., V.S.); and Experimental Animal Models for Aging Units, Research Department, INRCA IRRCS, Ancona, Italy (F.O.)

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.

Received December 10, 2007; accepted February 26, 2008

Address correspondence to: Dr. Naomi Balaban, Department of Biomedical Sciences, Cummings School of Veterinary Medicine, Tufts University, 200 Westboro Rd., North Grafton, MA 01536. E-mail: naomi.balaban{at}tufts.edu






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