Bioactivity-HiTES Unveils Cryptic Antibiotics Encoded in Actinomycete Bacteria.

TitleBioactivity-HiTES Unveils Cryptic Antibiotics Encoded in Actinomycete Bacteria.
Publication TypeJournal Article
Year of Publication2019
AuthorsMoon, K, Xu, F, Zhang, C, Seyedsayamdost, MR
JournalACS Chem Biol
Date Published2019 Apr 19
KeywordsActinobacteria, Anti-Bacterial Agents, Computational Biology, Drug Discovery, Genome, Bacterial, Multigene Family

<p>Bacteria harbor an immense reservoir of potentially new and therapeutic small molecules in the form of "silent" biosynthetic gene clusters (BGCs). These BGCs can be identified bioinformatically but are sparingly expressed under normal laboratory growth conditions, or not at all, and therefore do not produce significant levels of the corresponding small molecule product. Several methods have been developed for activating silent BGCs. A major limitation for nearly all methods is that they require genetic procedures and/or do not report on the bioactivity of the cryptic metabolite. We herein report "Bioactivty-HiTES", an approach that links the bioactivity of cryptic metabolites to their induction while at the same time obviating the need for genetic manipulations. Using this method, we detected induction of cryptic antibiotics in three actinomycete strains that were tested. Follow-up studies in one case allowed us to structurally elucidate two cryptic metabolites, elicited by the β-blocker atenolol in Streptomyces hiroshimensis, with selective growth-inhibitory activity against Gram-negative bacteria, notably Escherichia coli and Acinetobacter baumannii. Atenolol turned out to be a global elicitor of secondary metabolism, and characterization of additional cryptic metabolites led to the discovery of a novel naphthoquinone epoxide. Bioactivity-HiTES is a general, widely applicable procedure that will be useful in identifying cryptic bioactive metabolites in the future.</p>

Alternate JournalACS Chem Biol
PubMed ID30830740
PubMed Central IDPMC6813803
Grant ListDP2 AI124786 / AI / NIAID NIH HHS / United States