Investigation of Dipicolinic Acid Isosteres for the Inhibition of Metallo-β-Lactamases
| Autor: | Chen, Allie Y, Thomas, Pei W, Cheng, Zishuo, Xu, Nasa Y, Tierney, David L, Crowder, Michael W, Fast, Walter, Cohen, Seth M |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
imipenemase-1
Medicinal & Biomolecular Chemistry metallo-beta-lactamases Organic Chemistry Pharmacology and Pharmaceutical Sciences dipicolinic acid beta-Lactamases Zinc Inhibitory Concentration 50 Medicinal and Biomolecular Chemistry New Delhi metallo-β-lactamase 5.1 Pharmaceuticals isosteres metallo-β-lactamases metal binding pharmacophores New Delhi metallo-beta-lactamase Development of treatments and therapeutic interventions Picolinic Acids beta-Lactamase Inhibitors Protein Binding |
| Zdroj: | ChemMedChem, vol 14, iss 13 |
| Popis: | New Delhi metallo-β-lactamase-1 (NDM-1) poses an immediate threat to our most effective and widely prescribed drugs, the β-lactam-containing class of antibiotics. There are no clinically relevant inhibitors to combat NDM-1, despite significant efforts toward their development. Inhibitors that use a carboxylic acid motif for binding the ZnII ions in the active site of NDM-1 make up a large portion of the >500 inhibitors reported to date. New and structurally diverse scaffolds for inhibitor development are needed urgently. Herein we report the isosteric replacement of one carboxylate group of dipicolinic acid (DPA) to obtain DPA isosteres with good inhibitory activity against NDM-1 (and related metallo-β-lactamases, IMP-1 and VIM-2). It was determined that the choice of carboxylate isostere influences both the potency of NDM-1 inhibition and the mechanism of action. Additionally, we show that an isostere with a metal-stripping mechanism can be re-engineered into an inhibitor that favors ternary complex formation. This work provides a roadmap for future isosteric replacement of routinely used metal binding motifs (i.e., carboxylic acids) for the generation of new entities in NDM-1 inhibitor design and development. |
| Databáze: | OpenAIRE |
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