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

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.
Authors	Madanahally D Kiran, Nallini Vijayarangan Adikesavan, Oscar Cirioni, Andrea Giacometti, Carmela Silvestri, Giorgio Scalise, Roberto Ghiselli, Vittorio Saba, Fiorenza Orlando, Menachem Shoham, Naomi Balaban
Journal	Molecular pharmacology (Mol Pharmacol) Vol. 73 Issue 5 Pg. 1578-86 (May 2008) ISSN: 1521-0111 [Electronic] United States
PMID	18314496 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
Chemical References	Hemolysin Proteins Hexoses Oligopeptides RNA, Bacterial RNAIII inhibiting peptide RNAIII, Staphylococcus aureus Gallic Acid hamamelitannin
Topics	Animals Bacterial Adhesion (drug effects) Drug Evaluation, Preclinical Drug Resistance, Bacterial (drug effects) Gallic Acid (analogs & derivatives, chemistry, pharmacology) Hemolysin Proteins (metabolism) Hexoses (chemistry, pharmacology) Male Microbial Sensitivity Tests Models, Molecular Oligopeptides (chemistry) Prosthesis-Related Infections (microbiology) Quorum Sensing (drug effects) RNA, Bacterial (biosynthesis) Rats Rats, Wistar Staphylococcal Infections (microbiology) Staphylococcus (cytology, drug effects, growth & development)

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