National Academy of Sciences, Proceedings of the National Academy of Sciences, 16(117), p. 8850-8858, 2020
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Significance Nonribosomal peptides (NRPs) are a vast class of natural products and an important source of therapeutics. Typically, these secondary metabolites are assembled by NRP synthetases (NRPSs) that function on substrates covalently linked to the enzyme by a thioester, in a process known as thiotemplated biosynthesis. Although NRPS-independent assembly pathways are known, all are nonthiotemplated. Here we report an NRPS-independent yet thiotemplated pathway for NRP biosynthesis and demonstrate that members of the ATP-grasp and cysteine protease families form the β-peptide backbone of an antibiotic. Armed with this knowledge, we provide genomic evidence that this noncanonical assembly pathway is widespread in bacteria. Our results will inspire future genome mining efforts for the discovery of potential therapeutics that otherwise would be overlooked.