Lu Yanran, Papa Jonathan L, Nolan Sheri, English Anthony, Seffernick Justin T, Shkolnikov Nicholas, Powell Josh, Lindert Steffen, Wozniak Daniel J, Yalowich Jack, Mitton-Fry Mark J
Division of Medicinal Chemistry and Pharmacognosy.Division of Pharmaceutics and Pharmacology, Microbial Infection and Immunity, Department of Chemistry and Biochemistry, and Department of Microbiology, The Ohio State University, Columbus, Ohio 43210, United States.
ACS Med Chem Lett. 2020 Oct 19;11(12):2446-2454. doi: 10.1021/acsmedchemlett.0c00428. eCollection 2020 Dec 10.
In recent years, novel bacterial topoisomerase inhibitors (NBTIs) have been developed as future antibacterials for treating multidrug-resistant bacterial infections. A series of dioxane-linked NBTIs with an amide moiety has been synthesized and evaluated. Compound inhibits DNA gyrase, induces the formation of single strand breaks to bacterial DNA, and achieves potent antibacterial activity against a variety of Gram-positive pathogens, including methicillin-resistant (MRSA). Optimization of this series of analogues led to the discovery of a subseries of compounds (-) with more potent anti-MRSA activity, dual inhibition of DNA gyrase and topoisomerase IV, and the ability to induce double strand breaks through inhibition of DNA gyrase.
近年来，新型细菌拓扑异构酶抑制剂（NBTIs）已被开发为未来用于治疗多重耐药细菌感染的抗菌药物。一系列带有酰胺基团的二氧六环连接的NBTIs已被合成并评估。化合物抑制DNA促旋酶，诱导细菌DNA形成单链断裂，并对多种革兰氏阳性病原体，包括耐甲氧西林金黄色葡萄球菌（MRSA），具有强效抗菌活性。对这一系列类似物的优化导致发现了一个具有更强抗MRSA活性、对DNA促旋酶和拓扑异构酶IV双重抑制以及通过抑制DNA促旋酶诱导双链断裂能力的化合物子系列（-）。
