Department of Medicinal Chemistry, Center for Natural Products Drug Discovery and Development (CNPD3), College of Pharmacy, University of Florida, 1345 Center Dr., Gainesville, FL, 32610, USA.
Department of Molecular Genetics and Microbiology, College of Medicine, University of Florida, 1200 Newell Drive, Gainesville, FL, 32610, USA.
Sci Rep. 2017 May 17;7(1):2003. doi: 10.1038/s41598-017-01045-3.
Unlike individual, free-floating planktonic bacteria, biofilms are surface-attached communities of slow- or non-replicating bacteria encased within a protective extracellular polymeric matrix enabling persistent bacterial populations to tolerate high concentrations of antimicrobials. Our current antibacterial arsenal is composed of growth-inhibiting agents that target rapidly-dividing planktonic bacteria but not metabolically dormant biofilm cells. We report the first modular synthesis of a library of 20 halogenated phenazines (HP), utilizing the Wohl-Aue reaction, that targets both planktonic and biofilm cells. New HPs, including 6-substituted analogues, demonstrate potent antibacterial activities against MRSA, MRSE and VRE (MIC = 0.003-0.78 µM). HPs bind metal(II) cations and demonstrate interesting activity profiles when co-treated in a panel of metal(II) cations in MIC assays. HP 1 inhibited RNA and protein biosynthesis while not inhibiting DNA biosynthesis using H-radiolabeled precursors in macromolecular synthesis inhibition assays against MRSA. New HPs reported here demonstrate potent eradication activities (MBEC = 0.59-9.38 µM) against MRSA, MRSE and VRE biofilms while showing minimal red blood cell lysis or cytotoxicity against HeLa cells. PEG-carbonate HPs 24 and 25 were found to have potent antibacterial activities with significantly improved water solubility. HP small molecules could have a dramatic impact on persistent, biofilm-associated bacterial infection treatments.
与自由浮动的浮游细菌不同，生物膜是附着在表面的细菌群落，其缓慢或不复制的细菌被包裹在保护性的细胞外聚合基质中，使持久的细菌种群能够耐受高浓度的抗菌药物。我们目前的抗菌药物库由生长抑制剂组成，这些抑制剂针对快速分裂的浮游细菌，但不针对代谢休眠的生物膜细胞。我们报告了第一个利用 Wohl-Aue 反应合成的 20 个卤化苯并嗪（HP）的模块化文库，该文库针对浮游和生物膜细胞。包括 6 位取代的类似物在内的新 HP 对 MRSA、MRSE 和 VRE 具有很强的抗菌活性（MIC = 0.003-0.78 μM）。HP 可以结合金属（II）阳离子，并在 MIC 测定中与一系列金属（II）阳离子共同处理时表现出有趣的活性谱。HP1 通过使用 H 放射性标记的前体在针对 MRSA 的大分子合成抑制测定中抑制 RNA 和蛋白质的生物合成，而不抑制 DNA 的生物合成。本文报道的新 HP 对 MRSA、MRSE 和 VRE 生物膜具有很强的清除活性（MBEC = 0.59-9.38 μM），同时对 HeLa 细胞的红细胞溶解或细胞毒性最小。发现聚乙二醇碳酸酯 HP24 和 HP25 具有很强的抗菌活性，并且水溶性显著提高。HP 小分子可能会对持久的、与生物膜相关的细菌感染治疗产生巨大影响。
