Enaminone Formation Drives the Coupling of Biosynthetic Pathways to Generate Cyclic Lipopeptides

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. A group of enaminone‐containing cyclic lipopeptides were surprisingly found to be formed in microbial cells. The enaminone moiety results from the coupling of two biosynthetic pathways via amine‐aldehyde condensation.