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

The genome of Streptomyces indonesiensis is highly enriched with cryptic biosynthetic gene clusters (BGCs). The majority of these cryptic BGCs are transcriptionally silent in normal laboratory culture conditions as determined by transcriptome analysis. When cultured in acidic pH (pH 5.4), this strain has been shown to produce a set of new metabolites that were not observed in cultures of neutral pH (pH 7.4). The organic extract of the acidic culture displayed an antivirulence activity against methicillin-resistant Staphylococcus aureus (MRSA). Here, we report the structures of new glycosylated aromatic polyketides, named acidonemycins A-C (1-3), belonging to the family of angucyclines. Type II polyketide synthase 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 heterologous expression in Streptomyces albus J1074. Of the three new compounds, acidonemycins A and B (1 and 2) displayed antivirulence activity against MRSA. The simultaneous identification of both antivirulent compounds and their BGC provides a starting point for the future effort of combinatorial biosynthesis.