A family of novel cyclic lipopeptides named tasikamides A−H (Tsk A−H) were discovered recently in Streptomyces tasikensis P46. Aside from the unique cyclic pentapeptide scaffold shared by the tasikamides, Tsk A−C contain a hydrazone bridge that connects the cyclic pentapeptide to the lipophilic alkyl 5‐hydroxylanthranilate (AHA) moiety. Here we report the production of tasikamides I−K (Tsk I−K) by a mutant strain of S. tasikensis P46 that overexpresses two pathway‐specific transcription regulators. Unlike Tsk A−C, Tsk I−K feature a rare enaminone‐bridge that links the cyclic peptide scaffold to the AHA moiety. Our experimental data suggest that Tsk I−K are generated by the coupling of two biosynthetic pathways via a nonenzymatic condensation reaction between an arylamine and a β‐keto aldehyde‐containing precursor. The results underscore the nucleophilic and electrophilic reactivity of the β‐keto aldehyde moiety and its ability to promote fragment coupling reactions in live microbial cells.

Angucyclines are structurally diverse aromatic polyketides that have attracted considerable attention due to their potent bioactivity and intriguing biosynthetic origin. Balmoralmycin is a representative of a small family of angucyclines with unique structural features and an unknown biosynthetic origin.