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科学家发现一种不会产生耐药性的新型抗生素
作者:小柯机器人 发布时间:2020/6/5 14:16:50

美国普林斯顿大学Zemer Gitai研究组发现一种新型抗生素,可杀死革兰氏阴性菌并不会产生耐药。相关论文2020年6月3日在线发表于《细胞》。

研究人员表征了一种化合物SCH-79797,该化合物通过独特的双重靶向作用机制(MoA)杀死了革兰氏阴性和革兰氏阳性细菌,且耐药频率极低。为了表征其MoA,研究人员结合了定量成像、蛋白质组学、遗传学、代谢组学和基于细胞的检测方法。这些研究结果表明SCH-79797具有两个独立的细胞靶点,叶酸代谢和细菌膜完整性,并且在杀死耐甲氧西林的金黄色葡萄球菌(MRSA)方面优于联合治疗。
 
研究人员以SCH-79797的分子核心为基础,开发了具有增强功效的衍生物Irresistin-16,并在小鼠阴道感染模型中显示了其对淋病奈瑟氏球菌的功效。这种具有前景的抗生素表明,将多种MoA组合到单个化学框架上可能是治疗耐药细菌病原体的新方法。
 
据悉,抗生素耐药性的上升以及新抗生素发现数量的下降,造成了全球性的健康危机。特别值得关注的是,数十年来,没有新的抗生素类型被批准用于治疗革兰氏阴性病原体。
 
附:英文原文

Title: A Dual-Mechanism Antibiotic Kills Gram-Negative Bacteria and Avoids Drug Resistance

Author: James K. Martin, Joseph P. Sheehan, Benjamin P. Bratton, Gabriel M. Moore, André Mateus, Sophia Hsin-Jung Li, Hahn Kim, Joshua D. Rabinowitz, Athanasios Typas, Mikhail M. Savitski, Maxwell Z. Wilson, Zemer Gitai

Issue&Volume: 2020-06-03

Abstract: The rise of antibiotic resistance and declining discovery of new antibiotics has createda global health crisis. Of particular concern, no new antibiotic classes have beenapproved for treating Gram-negative pathogens in decades. Here, we characterize acompound, SCH-79797, that kills both Gram-negative and Gram-positive bacteria througha unique dual-targeting mechanism of action (MoA) with undetectably low resistancefrequencies. To characterize its MoA, we combined quantitative imaging, proteomic,genetic, metabolomic, and cell-based assays. This pipeline demonstrates that SCH-79797has two independent cellular targets, folate metabolism and bacterial membrane integrity,and outperforms combination treatments in killing methicillin-resistant Staphylococcus aureus (MRSA) persisters. Building on the molecular core of SCH-79797, we developed a derivative,Irresistin-16, with increased potency and showed its efficacy against Neisseria gonorrhoeae in a mouse vaginal infection model. This promising antibiotic lead suggests thatcombining multiple MoAs onto a single chemical scaffold may be an underappreciatedapproach to targeting challenging bacterial pathogens.

DOI: 10.1016/j.cell.2020.05.005

Source: https://www.cell.com/cell/fulltext/S0092-8674(20)30567-5

期刊信息
Cell:《细胞》,创刊于1974年。隶属于细胞出版社,最新IF:36.216
官方网址:https://www.cell.com/