5-Alkyl-1,2,3,4-tetrahydroquinolines, membrane-interacting lipophilic metabolites, found in a unique combined-culture of Streptomyces sp. HEK616 and Tsukamurella pulmonis

The cell membrane is one of the most challenging research subjects, partly because structure and function of lipid membranes are largely unknown at a molecular level. The chemical genetics approach using lipid-binding natural products is likely effective for understanding the cell membrane, however, most small molecules targeting membrane lipids exhibit acute toxicity and are not suitable for the live-cell analysis. To find new membrane-targeting molecules, we are screening microbial culture extracts using fission yeast mutant cells lacking sterol biosynthetic genes. Recently, 5-alkyl-1,2,3,4-tetrahydroquinolines (5aTHQs), novel tetrahydroquinoline alkaloids were discovered as new membrane-targeting molecules, from a unique combined-culture of Streptomyces and mycolic acid-containing bacteria.

The combined-culture of Streptomyces sp. HEK616 and Tsukamurella pulmonis exhibited anti-yeast activity in which ergosterol mutant cells showed higher tolerance than wild-type cells. Bioassay-guided fractionation afforded a dozen of novel alkaloids. Spectral analysis revealed that the molecules (5aTHQs) contained a 1,2,3,4-tetrahydroquinoline moiety to which an alkyl chain was attached at the position 5. In this presentation, we report the isolation, structure determination, synthesis and biological activity of 5aTHQs.