Graduate School of Pharmaceutical Sciences , The University of Tokyo , 7-3-1 Hongo , Bunkyo-ku , Tokyo 113-0033 , Japan.
Teikyo University Institute of Medical Mycology , 359 Otsuka , Hachioji , Tokyo 192-0395 , Japan.
J Org Chem. 2018 Jul 6;83(13):6924-6935. doi: 10.1021/acs.joc.7b02318. Epub 2017 Nov 7.
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 β-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.
WAP-8294A2（lotilibcin，1）是一种具有强大抗菌活性的抗生素，对耐甲氧西林金黄色葡萄球菌（MRSA）的体内疗效优于万古霉素。尽管具有重要的医学意义，但它的分子作用模式仍不清楚。在这里，我们报告了由 12 个氨基酸和一个 β-羟基脂肪酸链组成的复杂大环肽 1 及其脱氧类似物 2 的全合成。1 和 2 的完全固相合成使其能够快速组装，并首次对其功能进行了详细研究。化合物 1 和 2 对包括 MRSA 在内的各种革兰氏阳性菌具有同等的抗菌活性。我们提供的证据表明，1 和 2 的抗菌活性是由于细菌膜的裂解，并且它们的膜破坏作用取决于menaquinone 的存在，menaquinone 是细菌呼吸链的必需因素。所建立的合成途径和menaquinone 靶向机制为基于其结构设计和开发新型抗生素提供了有价值的信息。
