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靶向A型链霉菌素的抗生素可以克服Vat耐药性

来源:美高梅赌城网站作者:美高梅赌城网站 日期:2020-09-25 浏览:

本期文章:《自然》:Online/在线发表

美国加州大学Ian B. Seiple团队在研究中取得进展。他们发现靶向A型链霉菌素的抗生素可以克服弗吉尼亚霉素乙酰转移酶(Vat)的耐药性。相关论文于2020年9月23日在线发表于国际学术期刊《自然》。

研究人员对具有广泛结构变异A组链霉菌素抗生素的设计、合成和抗菌效价进行了评估。使用冷冻电镜和基于力场的细化,研究人员解析了八个类似物与细菌核糖体结合的高分辨率结构,揭示了延伸到肽酰tRNA结合位点并占据新生肽出核通道的结合相互作用。其中一种类似物对几种耐链霉菌素的金黄色葡萄球菌抗性菌株具有优异的杀伤,在体外降低乙酰化水平,并且在小鼠感染模型中显著降低菌载量。

该研究结果表明,合理设计与模块化化学合成相结合可以使受耐药机制限制的抗生素重新恢复杀伤力。

据介绍,天然产物可作为临床上大多数抗生素开发的基础。这些分子产生的进化过程伴随着耐药机制的进化,从而缩短了任何给定类别抗生素的临床寿命。Vat是抗性蛋白可抵抗链霉菌素,链霉菌素是抑制革兰氏阳性菌核糖体的有效抗生素。受到A组链霉菌素被选择性修饰化产生的23元大环骨架复合物的困扰,尚未研发出可以克服Vat酶抗性的类似物。

附:英文原文

Title: Synthetic group A streptogramin antibiotics that overcome Vat resistance

Author: Qi Li, Jenna Pellegrino, D. John Lee, Arthur A. Tran, Hector A. Chaires, Ruoxi Wang, Jesslyn E. Park, Kaijie Ji, David Chow, Na Zhang, Axel F. Brilot, Justin T. Biel, Gydo van Zundert, Kenneth Borrelli, Dean Shinabarger, Cindy Wolfe, Beverly Murray, Matthew P. Jacobson, Estelle Mhle, Olivier Chesneau, James S. Fraser, Ian B. Seiple

Issue&Volume: 2020-09-23

Abstract: Natural products serve as chemical blueprints for most antibiotics in clinical use. The evolutionary process by which these molecules arise is inherently accompanied by the co-evolution of resistance mechanisms that shorten the clinical lifetime of any given class of antibiotics1. Virginiamycin acetyltransferase (Vat) enzymes are resistance proteins that provide protection against streptogramins2, potent antibiotics against Gram-positive bacteria that inhibit the bacterial ribosome3. Owing to the challenge of selectively modifying the chemically complex, 23-membered macrocyclic scaffold of group A streptogramins, analogues that overcome the resistance conferred by Vat enzymes have not been previously developed2. Here we report the design, synthesis, and antibacterial evaluation of group A streptogramin antibiotics with extensive structural variability. Using cryo-electron microscopy and forcefield-based refinement, we characterize the binding of eight analogues to the bacterial ribosome at high resolution, revealing binding interactions that extend into the peptidyl tRNA-binding site and towards synergistic binders that occupy the nascent peptide exit tunnel. One of these analogues has excellent activity against several streptogramin-resistant strains of Staphylococcus aureus, exhibits decreased rates of acetylation in vitro, and is effective at lowering bacterial load in a mouse model of infection. Our results demonstrate that the combination of rational design and modular chemical synthesis can revitalize classes of antibiotics that are limited by naturally arising resistance mechanisms. Modular synthesis and structural biology are used to design and characterize group A streptogramin antibiotics, one of which has activity against streptogramin-resistant strains and demonstrates efficacy in a mouse model of bacterial infection.

DOI: 10.1038/s41586-020-2761-3

Source: https://www.nature.com/articles/s41586-020-2761-3

期刊信息

Nature:《自然》,创刊于1869年。隶属于施普林格·自然出版集团,最新IF:43.07
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