Discovery and Characterization of Oxazolismycin, an Oxazole-Containing Natural Product with an Atypical Loading Mechanism

Natural products (NPs) remain a vital source of bioactive molecules, with pyridine-containing compounds displaying diverse biological activities. This study presents the discovery of oxazolismycin, a novel pyridine-containing NP characterized by an oxazole-pyridine scaffold. Genome mining of Streptomyces griseochromogenes ATCC 14511 revealed a biosynthetic gene cluster encoding an NRPS-PKS assembly line homologous to those responsible for caerulomycin and collismycin biosynthesis. Gene knockouts and metabolite analysis of mutant strains unveiled the biosynthetic mechanism of oxazolismycin, including a previously uncharacterized β-ketoacyl-[acyl-carrier-protein] synthase III (KAS III), OxaC, which plays a noncanonical role in acyl group loading for NRPS initiation. Additionally, oxazolismycin exhibits notable angiotensin-converting enzyme (ACE) inhibition (IC₅₀= 0.326 ± 0.070 μM), suggesting its potential as a lead compound for ACE inhibitor development. These findings expand our understanding of pyridine-based NP biosynthesis, providing new insights into their enzymatic and structural diversity.