Identification of the common biosynthetic gene cluster for both antimicrobial streptoaminals and antifungal 5-alkyl-1,2,3,4-tetrahydroquinolines

Abstract

The new subfamily of type II PKS gene cluster is responsible for biosynthesis of structurally distinct streptoaminals (STAMs) and 5-alkyl-1,2,3,4-tetrahydroquinolines (5aTHQs).

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

“…WMMB-235 with Rhodococcus sp. [66] The former compounds exhibited inhibition towards fission yeast and might target membrane lipids,w hile the latter ones showed broad antimicrobial activities and their target for anti-yeast activity mayb ec ellular proteins.I nterestingly,t hese two classes of compounds with different structures and activities share ac ommon BGC, stm. [63] Among the successful cases, the potentialo fc ombined-culture for expanding chemical diversity of SMs is particularly attractive.…”

“…WMMA-185 resulted in the discoveryo fk eyicin, ana ntibiotic selectively active against gram positive bacteria. [66] The reduction states of the keto group in the alkyl starting units result in two distinct cyclization patterns to form STAMs and 5aTHQs, respectively.D uring the biosynthesis of 5aTHQs, ak etog roup at the C-9 position mayb ei nvolved, rather than ah ydroxyl group which is the case with STAMs. 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.…”

“…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. [66] The former compounds exhibited inhibition towards fission yeast and might target membrane lipids,w hile the latter ones showed broad antimicrobial activities and their target for anti-yeast activity mayb ec ellular proteins.I nterestingly,t hese two classes of compounds with different structures and activities share ac ommon BGC, stm. [66] The reduction states of the keto group in the alkyl starting units result in two distinct cyclization patterns to form STAMs and 5aTHQs, respectively.D uring the biosynthesis of 5aTHQs, ak etog roup at the C-9 position mayb ei nvolved, rather than ah ydroxyl group which is the case with STAMs.…”

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

“…Mycobacteria typically produce two sets of siderophores:water-soluble molecules and lipid-soluble ones. [17,18] Bioinformatic analyses and feeding experiments unveiled that the THQ ring and apart of the alkyl chain substituted at C-5 was revealed to be synthesized by aunique polyketide synthase machinery.V ariation of the terminal structure of the alkyl chain was speculated to be due to ad ifference in the starter unit. Another example is hydroxyalkylquinolines synthesized from the same biosynthetic pathway in Burkholderia thailandensis.…”

“…[13,14] Hydrophilic siderophores are thought to capture cytosolic iron ions and pass them to the lipid-soluble ones associated with lipid droplets in macrophage cells,t hus mycobacteria can collect iron efficiently during infection. [18] It was noted that the structure of the alkyl chain drastically affects the potencyo f the biological activity (Supporting Information, Figure S4): 5aTHQs with as hort alkyl chain (C 7 and C 8 ; 1-3)i nhibited growth of wild-type fission yeast Schizosaccharomyces pombe in the micromolar range,whereas 5aTHQs with anonyl group (4, 5)exhibited moderate activity.5aTHQs with adecyl group (6-8)oranundecyl group (9)showed weak or no activity even at 100 mm,d espite their significant abundance in the natural 5aTHQ mixture (Supporting Information, Figure S3). Tw or elated metabolites,4 -hydroxy-3-methyl-2-(2-nonenyl)-quinoline and 2-heptyl-4(1H)quinolone N-oxide,p ossessed overlapping cellular targets, and showed synergistic antibacterial effect.…”