Non-Nucleoside Inhibitors of BasE, an Adenylating Enzyme in the Siderophore Biosynthetic Pathway of the Opportunistic Pathogen Acinetobacter baumannii
| Autor: | Daniel J. Wilson, Curtis A. Engelhart, Eric J. Drake, rd Clifton E. Barry, Andrew M. Gulick, Courtney C. Aldrich, Helena I. Boshoff, João Neres, Peng Fu |
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| Rok vydání: | 2013 |
| Předmět: |
Acinetobacter baumannii
Models Molecular Siderophore Protein Conformation Klebsiella pneumoniae Siderophores Virulence Microbial Sensitivity Tests medicine.disease_cause Article Microbiology Structure-Activity Relationship Drug Discovery medicine Enzyme Inhibitors Escherichia coli chemistry.chemical_classification biology Pseudomonas aeruginosa biology.organism_classification Anti-Bacterial Agents Enzyme Biochemistry chemistry Molecular Medicine Bacteria |
| Zdroj: | Journal of Medicinal Chemistry. 56:2385-2405 |
| ISSN: | 1520-4804 0022-2623 |
| Popis: | Siderophores are small-molecule iron chelators produced by bacteria and other microorganisms for survival under iron limiting conditions such as found in a mammalian host. Siderophore biosynthesis is essential for the virulence of many important Gram-negative pathogens including Acinetobacter baumannii, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Escherichia coli. We performed high-throughput screening against BasE, which is involved in siderophore biosynthesis in A. baumannii, and identified 6-phenyl-1-(pyridin-4-ylmethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid 15. Herein we report the synthesis, biochemical, and microbiological evaluation of a systematic series of analogues of the HTS hit 15. Analogue 67 is the most potent analogue with a KD of 2 nM against BasE. Structural characterization of the inhibitors with BasE reveals that they bind in a unique orientation in the active site, occupying all three substrate binding sites, and thus can be considered as multisubstrate inhibitors. These results provide a foundation for future studies aimed at increasing both enzyme potency and antibacterial activity. |
| Databáze: | OpenAIRE |
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