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嵌合拟肽抗生素可杀死革兰氏阴性菌
2019-10-25 10:41

瑞士Polyphor AG公司Daniel Obrecht和John A. Robinson等研究人员报道了针对革兰氏阴性菌的嵌合拟肽抗生素。这一研究成果于2019年10月23日在线发表于国际学术期刊《自然》。

研究人员报道了一类受天然产物框架启发的合成抗生素。这些嵌合抗生素包含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-桶折叠复合物(BAM)的主要成分(BamA)结合,这是革兰氏阴性细菌中将β-桶蛋白质折叠和插入到其外膜所需的。广泛优化的衍生物显示出对多重耐药病原体(包括ESKAPE病原体的所有革兰氏阴性菌)有效的活性。这些衍生物在体外和体内也显示出良好的药物特性并克服了粘菌素抗性。

目前,主要候选药物正在临床前毒理学研究中,如果成功,它将使临床研究取得进展,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疗需求。

据悉,当前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。

附:英文原文

Title: Chimeric peptidomimetic antibiotics against Gram-negative bacteria

Author: Anatol Luther, Matthias Urfer, Michael Zahn, Maik Mller, Shuang-Yan Wang, Milon Mondal, Alessandra Vitale, Jean-Baptiste Hartmann, Timothy Sharpe, Fabio Lo Monte, Harsha Kocherla, Elizabeth Cline, Gabriella Pessi, Parthasarathi Rath, Seyed Majed Modaresi, Petra Chiquet, Sarah Stiegeler, Carolin Verbree, Tobias Remus, Michel Schmitt, Caroline Kolopp, Marie-Anne Westwood, Nicolas Desjonqures, Emile Brabet, Sophie Hell, Karen LePoupon, Annie Vermeulen, Rgis Jaisson, Virginie Rithi, Grgory Upert, Alexander Lederer, Peter Zbinden, Achim Wach, Kerstin Moehle, Katja Zerbe, Hans H. Locher, Francesca Bernardini, Glenn E. Dale, Leo Eberl, Bernd Wollscheid, Sebastian Hiller, John A. Robinson, Daniel Obrecht

Issue&Volume: 2019-10-23

Abstract: 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 β-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 β-barrel folding complex (BAM) that is required for the folding and insertion of β-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 pathogens1. 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.

DOI: 10.1038/s41586-019-1665-6

Source: https://www.nature.com/articles/s41586-019-1665-6

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
官方网址:http://www.nature.com/
投稿链接:http://www.nature.com/authors/submit_manuscript.html


本期文章:《自然》:Online/在线发表

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