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Endogenous Enzymes Enable Antimicrobial Activity

Cite this: ACS Chem. Biol. 2021, 16, 5, 800–805
Publication Date (Web):April 20, 2021
https://doi.org/10.1021/acschembio.0c00894
Copyright © 2021 American Chemical Society

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    Abstract

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    In light of the continued threat of antimicrobial-resistant bacteria, new strategies to expand the repertoire of antimicrobial compounds are necessary. Prodrugs are an underexploited strategy in this effort. Here, we report on the enhanced antimicrobial activity of a prodrug toward bacteria having an enzyme capable of its activation. A screen led us to the sulfurol ester of the antibiotic trans-3-(4-chlorobenzoyl)acrylic acid. An endogenous esterase makes Mycolycibacterium smegmatis sensitive to this prodrug. Candidate esterases were identified, and their heterologous production made Escherichia coli sensitive to the ester prodrug. Taken together, these data suggest a new approach to the development of antimicrobial compounds that takes advantage of endogenous enzymatic activities to target specific bacteria.

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    The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acschembio.0c00894.

    • Procedures for the synthesis of esters 210 and cognate esters with 2-thiopheneacetic acid; biological methods; annotated carboxylesterases in the sequence similarity network; esterase activity of bacterial cell lysates; screen of antimicrobial esters against E. coli and M. smegmatis; screen of alcohol compounds against E. coli, B. subtilis, and M. smegmatis; calibration of sulfurol ester:sulfurol peak-area ratio versus % hydrolyzed; LC–MS spectra and calibration curves of trans-3-(4-chlorobenzoyl)acrylic acid; determination of the e-value threshold for SSN; fit of viability curves of E. coli DH10B cells; extracted ion chromatograms of sulfurol ester 3 incubated in spent medium; NMR spectra (PDF)

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    Cited By

    This article is cited by 1 publications.

    1. Kenton J. Hetrick, Ronald T. Raines. Assessing and utilizing esterase specificity in antimicrobial prodrug development. 2022, 199-220. https://doi.org/10.1016/bs.mie.2021.11.008

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