科学家发现一种不会产生耐药性的新型抗生素 作者： 发布时间：/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, Andr Mateus, Sophia Hsin-Jung Li, Hahn Kim, Joshua D. Rabinowitz, Athanasios Typas, Mikhail M. Savitski, Maxwell Z. Wilson, Zemer Gitai
Issue Volume: -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..05.005
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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：投稿链接：
