Synthesis and kinetic testing of new inhibitors for a metallo-β-lactamase from Klebsiella pneumonia and Pseudomonas aeruginosa
| Autor: | Rania H. Abd El-Hameed, Peter Vella, Waleed M. Hussein, Ross P. McGeary, Gerhard Schenk, Mosaad S. Mohamed |
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| Rok vydání: | 2011 |
| Předmět: |
medicine.drug_class
Klebsiella pneumoniae Antibiotics medicine.disease_cause beta-Lactamases Microbiology Drug Discovery medicine Humans Structure–activity relationship Pseudomonas Infections Pyrroles Enzyme Inhibitors Escherichia coli Pharmacology chemistry.chemical_classification biology Pseudomonas aeruginosa Organic Chemistry Active site General Medicine medicine.disease biology.organism_classification Klebsiella Infections Enzyme Biochemistry chemistry biology.protein Klebsiella pneumonia beta-Lactamase Inhibitors |
| Zdroj: | European Journal of Medicinal Chemistry. 46:6075-6082 |
| ISSN: | 0223-5234 |
| DOI: | 10.1016/j.ejmech.2011.10.030 |
| Popis: | There are currently no clinically useful inhibitors against metallo-β-lactamases (MBLs), enzymes that confer resistance against a broad spectrum of commonly used antibiotics and that are produced by an increasing number of bacterial pathogens. New pyrrole derivatives were synthesized and assayed for their inhibitory effect on the catalytic activity of the IMP-1 MBL from Pseudomonas aeruginosa and Klebsiella pneumoniae . Six compounds tested ( 3a-3c , 5 , 7 and 8 ) show micromolar inhibition constants ( K i values range from ∼10 to 30 μM). In silico docking was employed to investigate the binding mode of the strongest inhibitor, 3b , in the active site of IMP-1. Implications for further improvements of binding efficiency and specificity are discussed. |
| Databáze: | OpenAIRE |
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