Natural products continue to provide valuable tools for chemical biology and lead compounds for drug discovery. They are secondary metabolites that can be subdivided according to their chemical structure as peptides, polysaccharides, isoprenoids, alkaloids, etc. Not only have these substances been optimized for a specific function during evolution, they also represent a promising basis for the development of compounds with novel bioactivities. One path to this goal is the artificial modification of natural product structures through organic synthesis. Our research group focuses on efficient, practical and flexible syntheses of biologically important natural molecules with architecturally complex structures. In this presentation, we report total synthesis and biological evaluation of the two peptide natural products, lysocin E (1) and WAP-8294A2 (lotilibcin, 2). Compounds 1 and 2 are 37-membered and 40-membered cyclic depsipeptide, respectively, and are potent antibiotics with superior in vivo efficacy to vancomycin against methicillin-resistant Staphylococcus aureus (MRSA). Therefore these peptides are expected to be promising seeds for MRSA treatment. First, we achieved the full solid-phase total synthesis of 1 and 2. Second, 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. Third, comprehensive structure-activity relationship (SAR) study of 1 was conducted 1) to investigate the side-chain functionalities relevant to the molecular mode of action and 2) to create more potent derivatives. The present studies provide valuable information for designing and developing new antibiotics based on their structures.

Total synthesis and biological evaluation of peptide natural products

256th National Meeting (2018)

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