Discovery and development of substituted thiadiazoles as inhibitors of Staphylococcus aureus Sortase A

[Display omitted] High-throughput screening of small-molecule libraries has led to the identification of thiadiazoles as a new class of inhibitors against Staphylococcus aureus sortase A (SrtA). N-(5-((4-nitrobenzyl)thio)-1,3,4-thiadiazol-2-yl)nicotinamide (IC50 = 3.8 µM) was identified as a potent...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry 2019-10, Vol.27 (19), p.115043-115043, Article 115043
Main Authors: Wehrli, Patrick M., Uzelac, Ivana, Olsson, Thomas, Jacso, Tomas, Tietze, Daniel, Gottfries, Johan
Format: Article
Language:English
Subjects:
accuracy
Anti-virulence drugs
Antimicrobial resistance
bacteria
Biochemistry & Molecular Biology
Biochemistry and Molecular Biology
Biokemi och molekylärbiologi
Chemistry
docking
Farmakologi och toxikologi
mechanism
Pharmacology & Pharmacy
Pharmacology and Toxicology
phosphines
resistance
side-chain
Sortase A
SrtA inhibitors
Staphylococcus aureus
surface-proteins
target
virulence
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Summary:[Display omitted] High-throughput screening of small-molecule libraries has led to the identification of thiadiazoles as a new class of inhibitors against Staphylococcus aureus sortase A (SrtA). N-(5-((4-nitrobenzyl)thio)-1,3,4-thiadiazol-2-yl)nicotinamide (IC50 = 3.8 µM) was identified as a potent inhibitor of SrtA after synthetic modification of hit compounds. Additional ligands developed in this study displayed affinities in the low micromolar range without affecting bacterial growth in vitro. The study also suggest a new mode of action through covalent binding to the active site cysteine.
ISSN:0968-0896
1464-3391
DOI:10.1016/j.bmc.2019.115043