title: Design, synthesis, and evaluation of fimbrolide-nitric oxide donor hybrids as antimicrobial agents.
abstract: Fimbrolides from marine algae have shown promising activity against quorum sensing (QS), a chief regulatory and communication system in bacteria controlling biofilm formation and virulence factor. Nitric oxide (NO) at sublethal concentration has also been reported to induce dispersal of bacterial biofilms and increase their susceptibility toward standard biocides and antibiotics. Therefore, the combination of QS inhibitors and NO donors has the potential to control the development of biofilm and promote their dispersion via a nonbactericidal mechanism. Inspired by these ideas, novel fimbrolide-NO donor hybrid compounds were designed and synthesized. Fimbrolide-NO hybrids 6b, 6f, and 14a were found to be particularly effective as antimicrobials compared to the nonhybrid natural fimbrolides as revealed by bioluminescent P. aeruginosa QS reporter assays and biofilm inhibition assays. Significantly, these fimbrolide-NO hybrids represent the first dual-action antimicrobial agent based on the baterial QS inhibition and NO signaling.
authors.affiliation: School of Chemistry, and ‡School of Biotechnology and Biomolecular Sciences and Centre for Marine Bio-Innovation, The University of New South Wales , Sydney, NSW 2052, Australia.
authors.forename: Samuel K
authors.initials: SK
authors.lastname: Kutty
authors.forename: Nicolas
authors.initials: N
authors.lastname: Barraud
authors.forename: Amy
authors.initials: A
authors.lastname: Pham
authors.forename: George
authors.initials: G
authors.lastname: Iskander
authors.forename: Scott A
authors.initials: SA
authors.lastname: Rice
authors.forename: David StC
authors.initials: DS
authors.lastname: Black
authors.forename: Naresh
authors.initials: N
authors.lastname: Kumar
mesh_terms: D015107:4-Butyrolactone / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000890:Anti-Infective Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D018441:Biofilms / Q000187:drug effects / Q000254:growth & development; D007783:Lactones / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D020030:Nitric Oxide Donors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D011550:Pseudomonas aeruginosa / Q000187:drug effects; D053038:Quorum Sensing / Q000187:drug effects*; D037521:Virulence Factors / Q000096:biosynthesis
chemical_list: D000890:Anti-Infective Agents; D007783:Lactones; D020030:Nitric Oxide Donors; D037521:Virulence Factors; D015107:4-Butyrolactone