NRPS Substrate Promiscuity Diversifies the Xenematides

[Image: see text] Xenematide, a cyclic depsipeptide antibiotic produced by Xenorhabdus nematophila, had a candidate nonribosomal peptide synthetase (NRPS) with atypical features. Differential metabolite analysis between a mutant and wildtype validated that this stand-alone NRPS was required for xenematide production, and further analysis led to a series of new xenematide derivatives encoded by the same NRPS. Our results indicate that adenylation domain promiscuity and relaxed downstream processing in the X. nematophila NRPS provide a conduit for xenematide diversification.