A New 1,2,3-Triazole Scaffold with Improved Potency against Staphylococcus aureus Biotin Protein Ligase

Staphylococcus aureus, a key ESKAPE bacteria, is responsible for most blood-based infections and, as a result, is a major economic healthcare burden requiring urgent attention. Here, we report in silico docking, synthesis, and assay of N1-diphenylmethyl triazole-based analogues (7–13) designed to in...

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Veröffentlicht in:ACS infectious diseases 2022-12, Vol.8 (12), p.2579-2585
Hauptverfasser: Stachura, Damian L., Nguyen, Stephanie, Polyak, Steven W., Jovcevski, Blagojce, Bruning, John B., Abell, Andrew D.
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container_end_page 2585
container_issue 12
container_start_page 2579
container_title ACS infectious diseases
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creator Stachura, Damian L.
Nguyen, Stephanie
Polyak, Steven W.
Jovcevski, Blagojce
Bruning, John B.
Abell, Andrew D.
description Staphylococcus aureus, a key ESKAPE bacteria, is responsible for most blood-based infections and, as a result, is a major economic healthcare burden requiring urgent attention. Here, we report in silico docking, synthesis, and assay of N1-diphenylmethyl triazole-based analogues (7–13) designed to interact with the entire binding site of S. aureus biotin protein ligase (SaBPL), an enzyme critical for the regulation of gluconeogenesis and fatty acid biosynthesis. The second aryl ring of these compounds enhances both SaBPL potency and whole cell activity against S. aureus relative to previously reported mono-benzyl triazoles. Analogues 12 and 13, with added substituents to better interact with the adenine binding site, are particularly potent, with K i values of 6.01 ± 1.01 and 8.43 ± 0.73 nM, respectively. These analogues are the most active triazole-based inhibitors reported to date and, importantly, inhibit the growth of a clinical isolate strain of S. aureus ATCC 49775, with minimum inhibitory concentrations of 1 and 8 μg/mL, respectively.
doi_str_mv 10.1021/acsinfecdis.2c00452
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source ACS Publications; MEDLINE
subjects Anti-Bacterial Agents - chemistry
Anti-Bacterial Agents - pharmacology
Bacterial Proteins - antagonists & inhibitors
Biotin
Carbon-Nitrogen Lyases - antagonists & inhibitors
Staphylococcus aureus - drug effects
Staphylococcus aureus - enzymology
Triazoles - chemistry
Triazoles - pharmacology
title A New 1,2,3-Triazole Scaffold with Improved Potency against Staphylococcus aureus Biotin Protein Ligase
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