Cell Chemical Biology
Volume 28, Issue 8, 19 August 2021, Pages 1242-1252.e4
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Bioreporters for direct mode of action-informed screening of antibiotic producer strains

https://doi.org/10.1016/j.chembiol.2021.02.022Get rights and content
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Highlights

  • Direct mode of action-informed bioreporter screening of antibiotic producer strains

  • Rapid mode of action profiling of unknown antimicrobials after overnight incubation

  • Detection of polypharmacology and synergism

  • Facilitated deconvolution process by an additional mode of action dimension

Summary

A big challenge in natural product research of today is rapid dereplication of already known substances, to free capacities for the exploration of new agents. Prompt information on bioactivities and mode of action (MOA) speeds up the lead discovery process and is required for rational compound optimization. Here, we present a bioreporter approach as a versatile strategy for combined bioactivity- and MOA-informed primary screening for antimicrobials. The approach is suitable for directly probing producer strains grown on agar, without need for initial compound enrichment or purification, and works along the entire purification pipeline with culture supernatants, extracts, fractions, and pure substances. The technology allows for MOA-informed purification to selectively prioritize activities of interest. In combination with high-resolution mass spectrometry, the biosensor panel is an efficient and sensitive tool for compound deconvolution. Concomitant information on the affected metabolic pathway enables the selection of appropriate follow-up assays to elucidate the molecular target.

Key words

biomarkers
activity-guided bioreporter screening
antibiotics
natural products
mode of action
profiling
antibiotic producer strains
actinomycetes
high-resolution mass spectrometry
dereplication

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