title: 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.affiliation: Department of Biomedical Sciences, Cummings School of Veterinary Medicine, Tufts University, 200 Westboro Rd., North Grafton, MA 01536, USA.
authors.forename: Madanahally D
authors.initials: MD
authors.lastname: Kiran
authors.forename: Nallini Vijayarangan
authors.initials: NV
authors.lastname: Adikesavan
authors.forename: Oscar
authors.initials: O
authors.lastname: Cirioni
authors.forename: Andrea
authors.initials: A
authors.lastname: Giacometti
authors.forename: Carmela
authors.initials: C
authors.lastname: Silvestri
authors.forename: Giorgio
authors.initials: G
authors.lastname: Scalise
authors.forename: Roberto
authors.initials: R
authors.lastname: Ghiselli
authors.forename: Vittorio
authors.initials: V
authors.lastname: Saba
authors.forename: Fiorenza
authors.initials: F
authors.lastname: Orlando
authors.forename: Menachem
authors.initials: M
authors.lastname: Shoham
authors.forename: Naomi
authors.initials: N
authors.lastname: Balaban
mesh_terms: D000818:Animals; D001422:Bacterial Adhesion / Q000187:drug effects; D004353:Drug Evaluation, Preclinical; D024881:Drug Resistance, Bacterial / Q000187:drug effects*; D005707:Gallic Acid / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D006460:Hemolysin Proteins / Q000378:metabolism; D006601:Hexoses / Q000737:chemistry* / Q000494:pharmacology*; D008297:Male; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D009842:Oligopeptides / Q000737:chemistry*; D016459:Prosthesis-Related Infections / Q000382:microbiology; D053038:Quorum Sensing / Q000187:drug effects*; D012329:RNA, Bacterial / Q000096:biosynthesis; D051381:Rats; D017208:Rats, Wistar; D013203:Staphylococcal Infections / Q000382:microbiology*; D013210:Staphylococcus / Q000166:cytology / Q000187:drug effects / Q000254:growth & development
chemical_list: D006460:Hemolysin Proteins; D006601:Hexoses; D009842:Oligopeptides; D012329:RNA, Bacterial; C111711:RNAIII inhibiting peptide; C096035:RNAIII, Staphylococcus aureus; D005707:Gallic Acid; C093412:hamamelitannin