Acidonemycins A-C, Glycosylated Angucyclines with Antivirulence Activity Produced by the Acidic Culture of Streptomyces indonesiensis

초록

Thegenome of Streptomyces indonesiensis is highlyenriched with cryptic biosynthetic gene clusters (BGCs). The majorityof these cryptic BGCs are transcriptionally silent in normal laboratoryculture conditions as determined by transcriptome analysis. When culturedin acidic pH (pH 5.4), this strain has been shown to produce a setof new metabolites that were not observed in cultures of neutral pH(pH 7.4). The organic extract of the acidic culture displayed an antivirulenceactivity against methicillin-resistant Staphylococcus aureus (MRSA). Here, we report the structures of new glycosylated aromaticpolyketides, named acidonemycins A-C (1-3), belonging to the family of angucyclines. Type II polyketidesynthase BGC responsible for the production of 1-3 was identified by a transcriptome comparison between acidic(pH 5.4) and neutral (pH 7.4) cultures and further confirmed by heterologousexpression in Streptomyces albus J1074. Of the threenew compounds, acidonemycins A and B (1 and 2) displayed antivirulence activity against MRSA. The simultaneousidentification of both antivirulent compounds and their BGC providesa starting point for the future effort of combinatorial biosynthesis.

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