Department of Medicinal Chemistry, College of Pharmacy, ‡Department of Molecular Genetics & Microbiology, College of Medicine, and ⊥Center for Natural Products, Drug Discovery and Development (CNPD3), University of Florida , Gainesville, Florida 32610.
J Med Chem. 2016 Apr 28;59(8):3808-25. doi: 10.1021/acs.jmedchem.5b02004. Epub 2016 Apr 6.
Persistent bacteria, including persister cells within surface-attached biofilms and slow-growing pathogens lead to chronic infections that are tolerant to antibiotics. Here, we describe the structure-activity relationships of a series of halogenated phenazines (HP) inspired by 2-bromo-1-hydroxyphenazine 1. Using multiple synthetic pathways, we probed diverse substitutions of the HP scaffold in the 2-, 4-, 7-, and 8-positions, providing critical information regarding their antibacterial and bacterial eradication profiles. Halogenated phenazine 14 proved to be the most potent biofilm-eradicating agent (≥99.9% persister cell killing) against MRSA (MBEC < 10 μM), MRSE (MBEC = 2.35 μM), and VRE (MBEC = 0.20 μM) biofilms while 11 and 12 demonstrated excellent antibacterial activity against M. tuberculosis (MIC = 3.13 μM). Unlike antimicrobial peptide mimics that eradicate biofilms through the general lysing of membranes, HPs do not lyse red blood cells. HPs are promising agents that effectively target persistent bacteria while demonstrating negligible toxicity against mammalian cells.
包括表面附着生物膜内的持久性细胞和生长缓慢的病原体在内的持续存在的细菌会导致对抗生素具有耐受性的慢性感染。在这里，我们描述了一系列受 2-溴-1-羟基吩嗪 1 启发的卤化吩嗪（HP）的结构-活性关系。通过多种合成途径，我们在 2-、4-、7-和 8-位探测了 HP 支架的各种取代基，提供了有关其抗菌和细菌清除特性的关键信息。卤化吩嗪 14 被证明是最有效的生物膜清除剂（对 MRSA（MBEC <10 μM）、MRSE（MBEC = 2.35 μM）和 VRE（MBEC = 0.20 μM）生物膜的持久性细胞杀伤率≥99.9%），而 11 和 12 对结核分枝杆菌（MIC = 3.13 μM）具有出色的抗菌活性。与通过普遍裂解膜来清除生物膜的抗菌肽模拟物不同，HP 不会裂解红细胞。HP 是一种很有前途的药物，可有效靶向持久性细菌，同时对哺乳动物细胞表现出可忽略不计的毒性。
