科學家發現一種不會產生耐藥性的新型抗生素
作者：
小柯機器人發布時間：2020/6/5 14:16:50
美國普林斯頓大學Zemer Gitai研究組發現一種新型抗生素，可殺死革蘭氏陰性菌並不會產生耐藥。相關論文2020年6月3日在線發表於《細胞》。
研究人員表徵了一種化合物SCH-79797，該化合物通過獨特的雙重靶向作用機制（MoA）殺死了革蘭氏陰性和革蘭氏陽性細菌，且耐藥頻率極低。為了表徵其MoA，研究人員結合了定量成像、蛋白質組學、遺傳學、代謝組學和基於細胞的檢測方法。這些研究結果表明SCH-79797具有兩個獨立的細胞靶點，葉酸代謝和細菌膜完整性，並且在殺死耐甲氧西林的金黃色葡萄球菌（MRSA）方面優於聯合治療。
研究人員以SCH-79797的分子核心為基礎，開發了具有增強功效的衍生物Irresistin-16，並在小鼠陰道感染模型中顯示了其對淋病奈瑟氏球菌的功效。這種具有前景的抗生素表明，將多種MoA組合到單個化學框架上可能是治療耐藥細菌病原體的新方法。
據悉，抗生素耐藥性的上升以及新抗生素發現數量的下降，造成了全球性的健康危機。特別值得關注的是，數十年來，沒有新的抗生素類型被批准用於治療革蘭氏陰性病原體。
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
Cell：《細胞》，創刊於1974年。隸屬於細胞出版社，最新IF：36.216