Ribosomally derived lipopeptides containing distinct fatty acyl moieties

Abstract

Significance Fatty-acylated lipopeptides are metabolites of high medical and biotechnological importance, exemplified by the clinically used daptomycin, polymyxin, and echinocandin anti-infectives. The known representatives are produced by giant nonribosomal enzymes that usually generate heterogeneously acylated peptides requiring elaborate procedures to obtain defined compounds. While a few interesting acylated, ribosomally synthesized peptides have been described, none of them use fatty acids in their biosynthesis. Computational and synthetic biology methods identified a cryptic family of ribosomal lipopeptides present in diverse bacteria. A multifaceted structure elucidation approach revealed specific and distinct fatty acylations of amino acid side chains for three pathways. The results bring the production of tailored, gene-encoded lipopeptides using minimalistic gene sets into reach and provide guidelines for synthetic biology–based discovery.