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.

中文翻译：

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WAP-8294A2的全合成和生物作用方式：一种针对甲萘醌的抗生素。

WAP-8294A2（lotilibcin，1）是一种强效抗生素，在体内具有优于万古霉素的耐甲氧西林金黄色葡萄球菌（MRSA）的功效。尽管医学上非常重要，但其分子作用方式仍然未知。在这里，我们报告了由12个具有β-羟基脂肪酸链的氨基酸组成的复杂大环肽1及其脱氧类似物2的总合成。1和2的完全固相合成使它们能够快速组装，并对其功能进行了首次详细研究。化合物1和2对包括MRSA在内的各种革兰氏阳性细菌菌株具有同等效力。我们目前的证据表明1和2的抗菌活性是由于细菌膜的溶解引起的，它们的膜破坏作用取决于甲萘醌的存在，甲萘醌是细菌呼吸链的重要因素。既定的合成途径和甲萘醌靶向机制为根据其结构设计和开发新抗生素提供了有价值的信息。