Total Synthesis and Biological Mode of Action of WAP-8294A2: A Menaquinone-Targeting Antibiotic
Total Synthesis and Biological Mode of Action of WAP-8294A2: A Menaquinone-Targeting Antibiotic
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DOI：
10.1021/acs.joc.7b02318
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发表时间：
2018-07-06
影响因子：
3.6
通讯作者：
Inoue, Masayuki
中科院分区：
文献类型：
--
作者：
Itoh, Hiroaki;Tokumoto, Kotaro;Inoue, Masayuki
WAP-8294A2是一种体内抗甲氧西林金黄色葡萄球菌(MRSA)疗效优于万古霉素的强效抗生素。尽管它在医学上具有重要意义，但其分子作用模式仍不清楚。本文报道了由12个氨基酸组成的含β-羟基脂肪链的大环肽1及其脱氧类似物2的全合成。1和2的全固相合成使它们的快速组装和功能的首次详细研究成为可能。化合物1和2对包括耐甲氧西林金黄色葡萄球菌在内的各种革兰氏阳性菌具有同等效力。我们提出的证据表明，1和2的抗菌活性是由于细菌膜的裂解，它们的膜破坏作用依赖于细菌呼吸链的一个重要因素--甲喹酮的存在。已建立的合成路线和孟喹酮靶向机制为根据其结构设计和开发新的抗生素提供了有价值的信息。
WAP-8294A2 (lotilibcin, 1) is a potent antibiotic with superior in vivo efficacy to vancomycin against methicillin-resistant Staphylococcus aureus (MRSA). Despite the great medical importance, its molecular mode of action remains unknown. Here we report the total synthesis of complex macrocyclic peptide 1 comprised of 12 amino acids with a beta-hydroxy fatty-acid chain, and its deoxy analogue 2. A full solid-phase synthesis of 1 and 2 enabled their rapid assembly and the first detailed investigation of their functions. Compounds 1 and 2 were equipotent against various strains of Gram-positive bacteria including MRSA. We present evidence that the antimicrobial activities of 1 and 2 are due to lysis of the bacterial membrane, and their membrane disrupting effects depend on the presence of menaquinone, an essential factor for the bacterial respiratory chain. The established synthetic routes and the menaquinone-targeting mechanisms provide valuable information for designing and developing new antibiotics based on their structures.