Structural and Mechanistic Insights into Atypical Bacterial Topoisomerase Inhibitors

IF 3.5 3区医学 Q2 CHEMISTRY, MEDICINAL

ACS Medicinal Chemistry Letters Pub Date : 2025-04-01 DOI:10.1021/acsmedchemlett.5c0006010.1021/acsmedchemlett.5c00060

Paul D. Toth, Steven C. Ratigan, Joshua W. Powell, Sydney R. Cassel, Jack C. Yalowich, Craig A. McElroy, Steffen Lindert, Charles E. Bell and Mark J. Mitton-Fry*,

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Abstract

Novel bacterial topoisomerase inhibitors (NBTIs) targeting DNA gyrase and topoisomerase IV constitute a new antibacterial class for deadly pathogens such as MRSA. While most NBTIs induce gyrase-mediated single-strand DNA breaks, a subset of amide NBTIs induces both single-strand and double-strand DNA breaks. Here, we report the X-ray crystal structures of two such amide NBTIs, 148 and 185, and demonstrate an unusual binding mode characterized by engagement of both GyrA D83 and R122. The synthesis of two isosteric triazole NBTIs is also described, one of which (342) affords only single-strand DNA breaks, while the other (276) also induces both single- and double-strand DNA breaks. A combination of docking and molecular dynamics simulations is employed to further investigate the potential structural underpinnings of differences in DNA cleavage.

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非典型细菌拓扑异构酶抑制剂的结构和机制研究

靶向DNA旋切酶和拓扑异构酶IV的新型细菌拓扑异构酶抑制剂（NBTIs）为MRSA等致命病原体提供了一类新的抗菌药物。虽然大多数nbti诱导螺旋酶介导的单链DNA断裂，但酰胺nbti的一个子集同时诱导单链和双链DNA断裂。在这里，我们报告了两种酰胺nbti的x射线晶体结构，148和185，并证明了一种不寻常的结合模式，其特征是GyrA D83和R122都参与。还描述了两种等构三唑nbti的合成，其中一种（342）仅提供单链DNA断裂，而另一种（276）也诱导单链和双链DNA断裂。结合对接和分子动力学模拟，进一步研究DNA切割差异的潜在结构基础。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

ACS Medicinal Chemistry Letters CHEMISTRY, MEDICINAL-

CiteScore

7.30

自引率

2.40%

发文量

328

审稿时长

1 months

期刊介绍： ACS Medicinal Chemistry Letters is interested in receiving manuscripts that discuss various aspects of medicinal chemistry. The journal will publish studies that pertain to a broad range of subject matter, including compound design and optimization, biological evaluation, drug delivery, imaging agents, and pharmacology of both small and large bioactive molecules. Specific areas include but are not limited to: Identification, synthesis, and optimization of lead biologically active molecules and drugs (small molecules and biologics) Biological characterization of new molecular entities in the context of drug discovery Computational, cheminformatics, and structural studies for the identification or SAR analysis of bioactive molecules, ligands and their targets, etc. Novel and improved methodologies, including radiation biochemistry, with broad application to medicinal chemistry Discovery technologies for biologically active molecules from both synthetic and natural (plant and other) sources Pharmacokinetic/pharmacodynamic studies that address mechanisms underlying drug disposition and response Pharmacogenetic and pharmacogenomic studies used to enhance drug design and the translation of medicinal chemistry into the clinic Mechanistic drug metabolism and regulation of metabolic enzyme gene expression Chemistry patents relevant to the medicinal chemistry field.