Abyssomicin biosynthesis: formation of an unusual polyketide, antibiotic-feeding studies and genetic analysis.

Abstract

Abyssomicin C, produced by the marine actinomycete Verrucosispora maris AB-18-032, is active against Gram-positive bacteria including methicillin-resistant Staphylococcus aureus (MRSA) and inhibits p-aminobenzoate formation during tetrahydrofolate synthesis; it is the first natural product active against this therapeutic target. To investigate the biosynthesis of this small but structurally complex secondary metabolite, we carried out feeding studies using 13C labelled polyketide building blocks. Formation of abyssomicin C requires two propionates, five acetates and one glucose-derived metabolite. Identification and sequencing of the abyssomicin biosynthetic gene cluster revealed a 57 kb segment of Verrucosispora maris AB-18-032 DNA that contained all of the genes necessary for abyssomicin biosynthesis. The identity of the biosynthetic gene cluster was confirmed by gene inactivation and complementation experiments (the first genetic manipulation of a member of this genus) and a model for abyssomicin C biosynthesis is proposed.