Molecular Editing Enhances Oxidation Resistance of Menaquinone‐Targeting Antibiotics Lysocin E and WAP‐8294A2

Abstract

AbstractLysocin E (1 a) and WAP‐8294A2 (2 a) are peptidic natural products with 37‐ and 40‐membered macrocycles, respectively. Compounds 1 a and 2 a have potent antibacterial activities against Gram‐positive bacteria and share a unique mode of action. The electron‐rich indole ring of d‐Trp‐10 of 1 a and 2 a interacts with the electron‐deficient benzoquinone ring of menaquinone, which is a co‐enzyme in the bacterial respiratory chain. Formation of the electron‐donor‐acceptor complex causes membrane disruption, leading to cell death. Despite the promising activities of 1 a and 2 a, the susceptibility of Trp‐10 to oxidative degradation potentially deters the development of these compounds as antibacterial drugs. To address this issue, we replaced the indole ring with more oxidation‐resistant aromatics having a similar shape and electron‐rich character. Specifically, analogues with benzofuran (1 b/2 b), benzothiophene (1 c/2 c), and 1‐naphthalene (1 d/2 d) rings were designed, and chemically prepared by full solid‐phase total syntheses. Antibacterial assays of the six analogues revealed similar activities of 1 d/2 d and markedly reduced activities of 1 b/2 b and 1 c/2 c compared with 1 a/2 a. Equipotent 1 d and 2 d both showed high resistance to oxidation by peroxyl radicals. Hence, the present study demonstrates a new molecular editing strategy for conferring oxidation stability on natural products with pharmacologically useful functions.