Chemical Interactions of Cryptic Actinomycete Metabolite 5‐Alkyl‐1,2,3,4‐tetrahydroquinolines through Aggregate Formation

Abstract

Organisms often produce secondary metabolites as amixture of biosynthetically related congeners.However,why are metabolites with minor chemical variations produced simultaneously?5 -Alkyl-1,2,3,4-tetrahydroquinolines (5aTHQs) are small, lipophilic metabolites produced by Streptomyces nigrescens HEK616 when cultured with Tsukamurella pulmonis TP-B0596. Am ixture of 5aTHQs forms aggregates that showenhanced membrane affinity and biological activity.T he ability to form aggregates and membranebinding activity is regulated by the length of the alkylc hains. Aggregates with long alkylc hains were too stable to fuse with lipid membranes.H owever,i fi nactive 5aTHQ congener was mixed with active congener,t he mixture showed increased membrane affinity,e nabling cellular entry and biological activity.Therefore,itisshown that sloppiness in abiosynthetic pathway,b yw hichm inor structural variations can be produced, is functionally rational, as the metabolites show synergistic action.

Cryptic Chemical Communication: Secondary Metabolic Responses Revealed by Microbial Co‐culture

“…We discoveredt wo kinds of closely related compounds, 5-alkyl-1,2,3,4-tetrahydroquinolines (5aTHQs) [64] and streptoaminals (STAMs), [65] which were isolated from the combined-culture brotho fS. [67] In another study,w ef ound that the combined-culture of Saccharothrix sp. 5aTHQsi nclude at least eight congeners with different alkyl side chains at the C-5 position of the planar THQ ring;s imilarly,t he only difference of six STAM congeners is the alkyl chains at the C-9 positiono ft he spirohemiaminal moiety.…”

“…Very recently,w er evealed a mixture of 5aTHQs aggregates that show enhanced membrane affinity and antifungal activity,s uggesting that sloppiness in the biosynthetic pathway,b yw hich minor structural variations can be produced, is functionally rational,a st he metabolites show synergistic action. [67] In another study,w ef ound that the combined-culture of Saccharothrix sp. A1506 with the TP-B0596s train significantly increased they ield of saccharothriolides [68] and stimulated the production of an ew congener,s accharothriolide C 2 .…”

“…Although the details of metabolic branching are still unclear, combined‐culture induced or enhanced the production of a total of 14 novel compounds in two classes. Very recently, we revealed a mixture of 5aTHQs aggregates that show enhanced membrane affinity and antifungal activity, suggesting that sloppiness in the biosynthetic pathway, by which minor structural variations can be produced, is functionally rational, as the metabolites show synergistic action …”