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Genome mining and heterologous expression of an orphan cluster led to the discovery of ashimides featuring an unusual cyclization mechanism., The ever-increasing bacterial genomic repositories reveal a great number of uncharacterized biosynthetic gene clusters, representing a tremendous resource for natural product discovery. Genome mining of the marine Streptomyces sp. NA03103 indicates the presence of an orphan nonribosomal peptide synthetase (NRPS) gene cluster (asm), to which there are no homologous gene clusters in the public genome databases. Heterologous expression of the asm gene cluster in the S. lividans SBT18 strain led to the discovery of two novel cyclopeptides, ashimides A and B (1 and 2), with 2 showing cytotoxic activity. In addition, we use bioinformatic analysis, gene inactivation and stable isotope labelling experiments, as well as in vitro biochemical assays, to present a coherent and novel assembly line for ashimide biosynthesis, featuring an unusual desaturation, halogenation and cyclization cascade catalyzed by a P450 monooxygenase and a FAD-dependent halogenase.

Two novel enediyne-derived natural products, amycolamycins A and B (1 and 2), were characterized from a locust-associated actinomycete Amycolatopsis sp. HCa4. Amycolamycins A and B contain a unique 2-(cyclopenta[a]inden-5-yl)oxirane core with suspected enediyne polyketide biosynthetic origin. Sequencing and analysis of the acm biosynthetic gene cluster allowed us to propose the biosynthetic pathway of 1 and 2. Moreover, amycolamycin A (1) was selectively cytotoxic to the M231 breast cancer cell line.