title: The Quorum Sensing Inhibitor Hamamelitannin Increases Antibiotic Susceptibility of Staphylococcus aureus Biofilms by Affecting Peptidoglycan Biosynthesis and eDNA Release.
abstract: Treatment of Staphylococcus aureus infections has become increasingly challenging due to the rapid emergence and dissemination of methicillin-resistant strains. In addition, S. aureus reside within biofilms at the site of infection. Few novel antibacterial agents have been developed in recent years and their bacteriostatic or bactericidal activity results in selective pressure, inevitably inducing antimicrobial resistance. Consequently, innovative antimicrobials with other modes of action are urgently needed. One alternative approach is targeting the bacterial quorum sensing (QS) system. Hamamelitannin (2',5-di-O-galloyl-d-hamamelose; HAM) was previously suggested to block QS through the TraP QS system and was shown to increase S. aureus biofilm susceptibility towards vancomycin (VAN) although mechanistic insights are still lacking. In the present study we provide evidence that HAM specifically affects S. aureus biofilm susceptibility through the TraP receptor by affecting cell wall synthesis and extracellular DNA release of S. aureus. We further provide evidence that HAM can increase the susceptibility of S. aureus biofilms towards different classes of antibiotics in vitro. Finally, we show that HAM increases the susceptibility of S. aureus to antibiotic treatment in in vivo Caenorhabditis elegans and mouse mammary gland infection models.
authors.affiliation: Laboratory of Pharmaceutical Microbiology, Faculty of Pharmaceutical Sciences, Ghent University, Ghent, Belgium.
authors.forename: Gilles
authors.initials: G
authors.lastname: Brackman
authors.affiliation: Laboratory of Biochemistry, Department of Pharmacology, Toxicology and Biochemistry, Faculty of Veterinary Medicine, Ghent University, Merelbeke, Belgium.
authors.forename: Koen
authors.initials: K
authors.lastname: Breyne
authors.affiliation: Inflammation Research Centre, VIB, Ghent, Belgium.|Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium.
authors.forename: Riet
authors.initials: R
authors.lastname: De Rycke
authors.affiliation: Laboratory for Medicinal Chemistry, Faculty of Pharmaceutical Sciences, Ghent University, Ghent, Belgium.
authors.forename: Arno
authors.initials: A
authors.lastname: Vermote
authors.affiliation: Laboratory of Pharmaceutical Biotechnology, Faculty of Pharmaceutical Sciences, Ghent University, Ghent, Belgium.
authors.forename: Filip
authors.initials: F
authors.lastname: Van Nieuwerburgh
authors.affiliation: Laboratory of Biochemistry, Department of Pharmacology, Toxicology and Biochemistry, Faculty of Veterinary Medicine, Ghent University, Merelbeke, Belgium.
authors.forename: Evelyne
authors.initials: E
authors.lastname: Meyer
authors.affiliation: Laboratory for Medicinal Chemistry, Faculty of Pharmaceutical Sciences, Ghent University, Ghent, Belgium.
authors.forename: Serge
authors.initials: S
authors.lastname: Van Calenbergh
authors.affiliation: Laboratory of Pharmaceutical Microbiology, Faculty of Pharmaceutical Sciences, Ghent University, Ghent, Belgium.
authors.forename: Tom
authors.initials: T
authors.lastname: Coenye
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D018441:Biofilms / Q000187:drug effects; D002473:Cell Wall / Q000378:metabolism; D004269:DNA, Bacterial / Q000378:metabolism*; D024881:Drug Resistance, Bacterial; D005110:Extracellular Space / Q000378:metabolism; D005707:Gallic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D006601:Hexoses / Q000494:pharmacology*; D008826:Microbial Sensitivity Tests; D009154:Mutation; D010457:Peptidoglycan / Q000096:biosynthesis*; D053038:Quorum Sensing / Q000187:drug effects / Q000235:genetics; D013211:Staphylococcus aureus / Q000187:drug effects* / Q000502:physiology*; D014774:Virulence; D037521:Virulence Factors / Q000235:genetics / Q000378:metabolism
chemical_list: D000900:Anti-Bacterial Agents; D004269:DNA, Bacterial; D006601:Hexoses; D010457:Peptidoglycan; D037521:Virulence Factors; D005707:Gallic Acid; C093412:hamamelitannin
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