menaquinone-6 and lotilibcin

Lysocin 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.

Topics: Anti-Bacterial Agents; Biological Products; Microbial Sensitivity Tests; Vitamin K 2

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.

Topics: Anti-Infective Agents; Candida; Cryptococcus neoformans; Depsipeptides; Gram-Negative Bacteria; Gram-Positive Bacteria; Membrane Potentials; Microbial Sensitivity Tests; Vitamin K 2