GmhA 抑制剂对革兰氏阴性细菌的增效作用

IF 6.8 1区 医学 Q1 CHEMISTRY, MEDICINAL
François Moreau, Dmytro Atamanyuk, Markus Blaukopf, Marek Barath, Mihály Herczeg, Nuno M. Xavier, Jérôme Monbrun, Etienne Airiau, Vivien Henryon, Frédéric Leroy, Stéphanie Floquet, Damien Bonnard, Robert Szabla, Chris Brown, Murray S. Junop, Paul Kosma* and Vincent Gerusz*, 
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引用次数: 0

摘要

抑制细菌庚糖的生物合成为抗菌疗法开辟了新的前景。负责第一个生物合成步骤的 GmhA 酶催化 7-磷酸色酮糖转化为 7-磷酸 d-甘油-d-甘露庚糖,其活性位点含有一个 Zn2+ 离子。我们设计并从适当保护的核糖或己糖衍生物中制备了一系列具有羟基氨基甲酸酯分子的磷酰基和膦酰基取代衍生物。GmhA 与两种 N-甲酰基羟基氨基甲酸酯抑制剂复合物的高分辨率晶体结构证实了与中心 Zn2+ 离子配位位点的结合相互作用。其中一些化合物被发现是纳摩尔级的 GmhA 抑制剂。虽然这些化合物本身不具有 HepG2 细胞毒性和抗菌活性,但它们在体外对肠杆菌的脂多糖庚基化有抑制作用,并在野生型大肠杆菌菌株中对红霉素和利福平有增效作用。这些抑制剂为治疗革兰氏阴性菌感染铺平了道路。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Potentiating Activity of GmhA Inhibitors on Gram-Negative Bacteria

Potentiating Activity of GmhA Inhibitors on Gram-Negative Bacteria

Potentiating Activity of GmhA Inhibitors on Gram-Negative Bacteria

Inhibition of the biosynthesis of bacterial heptoses opens novel perspectives for antimicrobial therapies. The enzyme GmhA responsible for the first committed biosynthetic step catalyzes the conversion of sedoheptulose 7-phosphate into d-glycero-d-manno-heptose 7-phosphate and harbors a Zn2+ ion in the active site. A series of phosphoryl- and phosphonyl-substituted derivatives featuring a hydroxamate moiety were designed and prepared from suitably protected ribose or hexose derivatives. High-resolution crystal structures of GmhA complexed to two N-formyl hydroxamate inhibitors confirmed the binding interactions to a central Zn2+ ion coordination site. Some of these compounds were found to be nanomolar inhibitors of GmhA. While devoid of HepG2 cytotoxicity and antibacterial activity of their own, they demonstrated in vitro lipopolysaccharide heptosylation inhibition in Enterobacteriaceae as well as the potentiation of erythromycin and rifampicin in a wild-type Escherichia coli strain. These inhibitors pave the way for a novel treatment of Gram-negative infections.

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来源期刊
Journal of Medicinal Chemistry
Journal of Medicinal Chemistry 医学-医药化学
CiteScore
4.00
自引率
11.00%
发文量
804
审稿时长
1.9 months
期刊介绍: The Journal of Medicinal Chemistry is a prestigious biweekly peer-reviewed publication that focuses on the multifaceted field of medicinal chemistry. Since its inception in 1959 as the Journal of Medicinal and Pharmaceutical Chemistry, it has evolved to become a cornerstone in the dissemination of research findings related to the design, synthesis, and development of therapeutic agents. The Journal of Medicinal Chemistry is recognized for its significant impact in the scientific community, as evidenced by its 2022 impact factor of 7.3. This metric reflects the journal's influence and the importance of its content in shaping the future of drug discovery and development. The journal serves as a vital resource for chemists, pharmacologists, and other researchers interested in the molecular mechanisms of drug action and the optimization of therapeutic compounds.
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