Department of Medicinal Chemistry, Center for Natural Products, Drug Discovery and Development (CNPD3), College of Pharmacy, University of Florida, Gainesville, Florida 32610, USA.
Department of Molecular Genetics & Microbiology, College of Medicine, University of Florida, Gainesville, Florida 32610, USA.
Org Biomol Chem. 2021 Aug 5;19(30):6603-6608. doi: 10.1039/d1ob01107c.
Antibiotic-resistant infections present significant challenges to patients. As a result, there is considerable need for new antibacterial therapies that eradicate pathogenic bacteria through non-conventional mechanisms. Our group has identified a series of halogenated phenazine (HP) agents that induce rapid iron starvation that leads to potent killing of methicillin-resistant Staphylococcus aureus biofilms. Here, we report the design, chemical synthesis and microbiological assessment of a HP-quinone ether prodrug model aimed to (1) eliminate general (off-target) iron chelation, and (2) release an active HP agent through the bioreduction of a quinone trigger. Here, we demonstrate prodrug analogue HP-29-Q to have a stable ether linkage that enables HP release and moderate to good antibacterial activities against lab strains and multi-drug resistant clinical isolates.
耐药感染对患者构成重大挑战。因此，非常需要新的抗菌疗法，这些疗法通过非传统机制消灭致病菌。我们小组已经确定了一系列卤化吩嗪 (HP) 试剂，它们能快速诱导铁饥饿，从而有效杀死耐甲氧西林金黄色葡萄球菌生物膜。在这里，我们报告了一种 HP-醌醚前药模型的设计、化学合成和微生物评估，旨在 (1) 消除一般（非靶向）铁螯合，和 (2) 通过醌触发物的生物还原释放活性 HP 试剂。在这里，我们证明前药类似物 HP-29-Q 具有稳定的醚键，能够释放 HP，并对实验室菌株和多药耐药临床分离株具有中等至良好的抗菌活性。
