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- W3100136504 abstract "ABSTRACT Multi-drug resistant bacteria present an urgent threat to modern medicine, creating a desperate need for the discovery of antibiotics with new modes of action. Natural products whose unique highly diverse structures have been shaped by evolution to possess biologically relevant activity are an ideal discovery ground for new antibiotics with new mechanisms of action. In this study we elucidate the mechanism of action of the Gram-positive antibiotic armeniaspirol, a compound for which resistant bacteria could not be selected for. We show that armeniaspirol inhibits the ATP-dependent proteases ClpXP and ClpYQ in biochemical assays and in the Gram-positive bacteria Bacillus subtilis. We then show that this activity dysregulates key proteins involved in the divisome and elongasome including FtsZ, DivIVA, and MreB all of which are known to inhibit cell division when upregulated. Inhibition of ClpXP and ClpYQ leading to dysregulation of the divisome and elongasome represents a new mechanism of action and armeniaspirol is the first known natural product inhibitor of the coveted anti-virulence target ClpP. Thus armeniaspirol is the lead compound for a promising new class of antibiotics with a unique pharmacology and a novel mechanism for combating antimicrobial resistance, making it a highly promising candidate for further development." @default.
- W3100136504 created "2020-11-23" @default.
- W3100136504 creator A5017585282 @default.
- W3100136504 creator A5052667915 @default.
- W3100136504 creator A5053298701 @default.
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- W3100136504 creator A5067862836 @default.
- W3100136504 creator A5076663151 @default.
- W3100136504 creator A5077288231 @default.
- W3100136504 date "2019-06-28" @default.
- W3100136504 modified "2023-09-24" @default.
- W3100136504 title "Armeniaspirols inhibit the AAA+ proteases ClpXP and ClpYQ leading to cell division arrest in Gram-positive bacteria" @default.
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