title: Chemical trapping of vancomycin: a potential strategy for preventing selection of vancomycin-resistant Enterococci.
abstract: Emergence of antimicrobial resistance is among the most worrisome issues in public health worldwide. Vancomycin resistance is rapidly spreading, resulting in increased morbidity, mortality, and healthcare-associated costs. Multiple strategies are required to preserve the effectiveness of this essential antibiotic. It has been recently shown that biliary excretion of vancomycin following parenteral administration results in significant fecal concentrations of vancomycin that may lead to selection of vancomycin-resistant strains within the colon. In this study we present a novel strategy for preventing this undesired effect and its consequences, using chemical trapping of vancomycin by a tripeptide analog that mimics the natural bacterial vancomycin binding-site. Initially, we demonstrated that a tripeptide analog can neutralize vancomycin activity against Enterococci at a molar excess of 28. In the second phase, two chemical modifications, designed to attach the tripeptide to vancomycin covalently, were explored. Attachment of a 4-flurosulfonyl-benzoic acid (FSBA) moiety to the parent tripeptide resulted in vancomycin neutralization at a molar ratio of less than 4:1. Finally it was shown that the FSBA-bound tripeptide analog can prevent in-vitro selection of vancomycin-resistant Enterococci (VRE) from a mixed vancomycin susceptible/resistant population following exposure to vancomycin. These findings demonstrate the ability of the proposed strategy to prevent selection of VRE. The present proof-of-concept study provides the basis for further development of the proposed strategy. Further, this strategy may be implemented for combating resistance to other antimicrobials.
authors.affiliation: Department of Pharmaceutics, School of Pharmacy, Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel. ehud.horwitz@mail.huji.ac.il
authors.forename: Ehud
authors.initials: E
authors.lastname: Horwitz
authors.forename: Yftah
authors.initials: Y
authors.lastname: Tal-Gan
authors.forename: Violetta
authors.initials: V
authors.lastname: Temper
authors.forename: Mervyn
authors.initials: M
authors.lastname: Shapiro
authors.forename: Chaim
authors.initials: C
authors.lastname: Gilon
authors.forename: Amnon
authors.initials: A
authors.lastname: Hoffman
mesh_terms: D000900:Anti-Bacterial Agents / Q000737:chemistry* / Q000494:pharmacology; D001665:Binding Sites; D016983:Enterococcus / Q000187:drug effects / Q000378:metabolism; D005243:Feces / Q000382:microbiology; D006801:Humans; D009842:Oligopeptides / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D014640:Vancomycin / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D020713:Vancomycin Resistance / Q000187:drug effects*
chemical_list: D000900:Anti-Bacterial Agents; D009842:Oligopeptides; D014640:Vancomycin