Discovery and development of substituted thiadiazoles as inhibitors of Staphylococcus aureus Sortase A |
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| Institution: | 1. Institute of Drug Metabolism and Pharmaceutical Analysis and Zhejiang Provincial Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China;2. College of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou 310053, China;3. Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, United States;4. Formulation and Analysis Laboratory, Hisun Pharma (Hangzhou) Co. Ltd., Hangzhou 311404, China |
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| Abstract: | 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. |
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| Keywords: | Sortase A SrtA inhibitors Anti-virulence drugs Antimicrobial resistance |
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