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.