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Chimeric peptidomimetic antibiotics against Gram-negative bacteria

机译：用于革兰氏阴性菌的嵌合拟肽抗生素

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摘要

There is an urgent need for new antibiotics against Gram-negative pathogens that are resistant to carbapenem and third-generation cephalosporins, against which antibiotics of last resort have lost most of their efficacy. Here we describe a class of synthetic antibiotics inspired by scaffolds derived from natural products. These chimeric antibiotics contain a beta-hairpin peptide macrocycle linked to the macrocycle found in the polymyxin and colistin family of natural products. They are bactericidal and have a mechanism of action that involves binding to both lipopolysaccharide and the main component (BamA) of the beta-barrel folding complex (BAM) that is required for the folding and insertion of beta-barrel proteins into the outer membrane of Gram-negative bacteria. Extensively optimized derivatives show potent activity against multidrug-resistant pathogens, including all of the Gram-negative members of the ESKAPE pathogens(1). These derivatives also show favourable drug properties and overcome colistin resistance, both in vitro and in vivo. The lead candidate is currently in preclinical toxicology studies that-if successful-will allow progress into clinical studies that have the potential to address life-threatening infections by the Gram-negative pathogens, and thus to resolve a considerable unmet medical need.
机译：迫切需要针对革兰氏阴性病原体的新型抗生素，这些抗生素对碳青霉烯和第三代头孢菌素具有耐药性，而最后一种抗生素已失去了大部分功效。在这里，我们描述了一类受天然产物支架启发的合成抗生素。这些嵌合抗生素含有与天然产物多粘菌素和粘菌素家族中发现的大环相连的β-发夹肽大环。它们具有杀菌作用，其作用机理包括与脂多糖和β-桶状折叠复合物（BAM）的主要成分（BamA）结合，这是将β-桶状蛋白质折叠和插入其外膜所需的。革兰氏阴性细菌。广泛优化的衍生物显示出对耐多药病原体的有效活性，包括ESKAPE病原体的所有革兰氏阴性菌（1）。这些衍生物在体外和体内也显示出有利的药物特性并克服了粘菌素抗性。目前，主要的候选对象是临床前毒理学研究，如果成功，将可以进行临床研究，从而有可能解决革兰氏阴性病原体威胁生命的感染，从而解决相当大的未满足的医学需求。

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