Design, Synthesis, and Evaluation of Fimbrolide鈥揘itric Oxide Donor Hybrids as Antimicrobial Agents

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• 作者：Samuel K. Kutty ; Nicolas Barraud ; Amy Pham ; George Iskander ; Scott A. Rice ; David StC. Black ; Naresh Kumar
• 刊名：Journal of Medicinal Chemistry
• 出版年：2013
• 出版时间：December 12, 2013
• 年：2013
• 卷：56
• 期：23
• 页码：9517-9529
• 全文大小：525K
• 年卷期：v.56,no.23(December 12, 2013)
• ISSN：1520-4804

文摘

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鈥揘O donor hybrid compounds were designed and synthesized. Fimbrolide鈥揘O 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鈥揘O hybrids represent the first dual-action antimicrobial agent based on the baterial QS inhibition and NO signaling.