Activity-Independent Discovery of Secondary Metabolites Using Chemical Elicitation and Cheminformatic Inference

ACS Chemical Biology
Sheila M Pimentel-ElardoJustin Nodwell

Abstract

Most existing antibiotics were discovered through screens of environmental microbes, particularly the streptomycetes, for the capacity to prevent the growth of pathogenic bacteria. This "activity-guided screening" method has been largely abandoned because it repeatedly rediscovers those compounds that are highly expressed during laboratory culture. Most of these metabolites have already been biochemically characterized. However, the sequencing of streptomycete genomes has revealed a large number of "cryptic" secondary metabolic genes that are either poorly expressed in the laboratory or that have biological activities that cannot be discovered through standard activity-guided screens. Methods that reveal these uncharacterized compounds, particularly methods that are not biased in favor of the highly expressed metabolites, would provide direct access to a large number of potentially useful biologically active small molecules. To address this need, we have devised a discovery method in which a chemical elicitor called Cl-ARC is used to elevate the expression of cryptic biosynthetic genes. We show that the resulting change in product yield permits the direct discovery of secondary metabolites without requiring knowledge of their b...Continue Reading

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Citations

Sep 1, 2016·FEMS Microbiology Reviews·Bethany K Okada, Mohammad R Seyedsayamdost
Jan 12, 2017·ACS Chemical Biology·Martin Daniel-IvadJustin R Nodwell
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Aug 27, 2019·Frontiers in Microbiology·Jonathan L KlassenKi Hyun Kim
May 5, 2021·Microbiology·Vanessa Yoon CalveloJustin Rea Nodwell

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