Dissecting the biosynthesis of the polyketide alkaloid lydicamycin using a complex metabolic network

Abstract

Microorganisms produce a great number of therapeutically interesting and structurally diverse natural products through modular biosynthetic assembly lines, i.e., type I polyketide synthases (PKSs) and nonribosomal peptide synthetases (NRPSs). Lydicamycins are polyketide antibiotics belonging to a family of hybrid nonribosomal peptide-polyketide scaffolds that possess unique tetramic acid and pyrrolidine moieties at each end of their structures. To date, only five lydicamycin congeners have been isolated by sophisticated chemistry or bioactivity-guided approaches. In this work, we report the biosynthetic gene cluster of lydicamycins and fully characterize all congeners, including previously unreported compounds from one pathway, through molecular networking. The results indicate that the chemical potential of the congeners in this family is far from being fully described. Our findings will provide new insights into the enzymatic machinery during hybrid PKS–NRPS biosynthesis and might be applied to rationalize bioengineering processes for other similar homologues.