Gao Qiwen, Yang Hongfen, Sheiber Jeremy, Bartolomeu Halicki Priscila Cristina, Liu Ke, Blanco David, Milhous Sadie, Jin Shouguang, Rohde Kyle H, Fleeman Renee M, Huigens Iii Robert W
Department of Pharmaceutical & Biomedical Sciences, College of Pharmacy, University of Georgia, Athens, Georgia 30602, USA.
Department of Medicinal Chemistry, Center for Natural Products, Drug Discovery and Development (CNPD3), College of Pharmacy, University of Florida, Gainesville, Florida 32610, USA.
Org Biomol Chem. 2025 Apr 2;23(14):3342-3357. doi: 10.1039/d4ob02011a.
Bacterial biofilms are surface-attached communities consisting of non-replicating persister cells encased within an extracellular matrix of biomolecules. Unlike bacteria that have acquired resistance to antibiotics, persister cells enable biofilms to demonstrate innate tolerance toward all classes of conventional antibiotic therapies. It is estimated that 50-80% of bacterial infections are biofilm associated, which is considered the underlying cause of chronic and recurring infections. Herein, we report a modular three-step synthetic route to new halogenated phenazine (HP) analogues from diverse aniline and nitroarene building blocks. The HPs were evaluated for antibacterial and biofilm-killing properties against a panel of lab strains and multidrug-resistant clinical isolates. Several HPs demonstrated potent antibacterial (MIC ≤ 0.39 μM) and biofilm-eradicating activities (MBEC < 10 μM) with 6,8-ditrifluoromethyl-HP 15 demonstrated remarkable biofilm-killing potencies (MBEC = 0.15-1.17 μM) against Gram-positive pathogens, including methicillin-resistant clinical isolates. Confocal microscopy showed HP 15 induced significant losses in the polysaccharide matrix in MRSA biofilms. In addition, HP 15 showed increased antibacterial activities against dormant (, MIC = 1.35 μM) when compared to replicating (MIC = 3.69 μM). Overall, this new modular route has enabled rapid access to an interesting series of potent halogenated phenazine analogues to explore their unique antibacterial and biofilm-killing properties.
细菌生物膜是附着于表面的群落，由包裹在生物分子细胞外基质中的非复制型持留细胞组成。与已获得抗生素耐药性的细菌不同，持留细胞使生物膜能够对所有常规抗生素疗法表现出固有耐受性。据估计，50 - 80%的细菌感染与生物膜相关，这被认为是慢性和复发性感染的根本原因。在此，我们报道了一种模块化的三步合成路线，可从多种苯胺和硝基芳烃构建块合成新的卤代吩嗪（HP）类似物。对这些HP类似物针对一系列实验室菌株和多重耐药临床分离株的抗菌和杀生物膜特性进行了评估。几种HP类似物表现出强效抗菌活性（MIC≤0.39μM）和生物膜根除活性（MBEC < 10μM），其中6,8 - 二（三氟甲基）- HP 15对包括耐甲氧西林临床分离株在内的革兰氏阳性病原体表现出显著的杀生物膜效力（MBEC = 0.15 - 1.17μM）。共聚焦显微镜显示HP 15可使耐甲氧西林金黄色葡萄球菌生物膜中的多糖基质显著减少。此外，与繁殖型细菌（MIC = 3.69μM）相比，HP 15对休眠型细菌（MIC = 1.35μM）的抗菌活性增强。总体而言，这种新的模块化路线能够快速获得一系列有趣的强效卤代吩嗪类似物，以探索它们独特的抗菌和杀生物膜特性。
