Total Synthesis and Biological Mode of Action of WAP-8294A2: A Menaquinone-Targeting Antibiotic

Hiroaki Itoh, Kotaro Tokumoto, Takuya Kaji, Atmika Paudel, Suresh Panthee, Hiroshi Hamamoto, Kazuhisa Sekimizu, Masayuki Inoue

Research output: Contribution to journalArticle

11 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)6924-6935
Number of pages12
JournalJournal of Organic Chemistry
Volume83
Issue number13
DOIs
Publication statusPublished - 2018 Jul 6
Externally publishedYes

ASJC Scopus subject areas

  • Organic Chemistry

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    Itoh, H., Tokumoto, K., Kaji, T., Paudel, A., Panthee, S., Hamamoto, H., Sekimizu, K., & Inoue, M. (2018). Total Synthesis and Biological Mode of Action of WAP-8294A2: A Menaquinone-Targeting Antibiotic. Journal of Organic Chemistry, 83(13), 6924-6935. https://doi.org/10.1021/acs.joc.7b02318