Dual-Target Inhibitors of the Folate Pathway Inhibit Intrinsically Trimethoprim-Resistant DfrB Dihydrofolate Reductases
| Autor: | Delphine Forge, Xinhua Ji, Jean Jacques Vanden Eynde, Maximilian C. C. J. C. Ebert, Jacynthe L. Toulouse, Ruediger Edward H, Deon Daniel H, Marc Gagnon, Genbin Shi, Claudèle Lemay-St-Denis, Anne Marinier, Kévin Saint-Jacques, Joelle N. Pelletier |
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| Rok vydání: | 2020 |
| Předmět: |
chemistry.chemical_classification
Dual target Type II dihydrofolate reductase 010405 organic chemistry Organic Chemistry urologic and male genital diseases bacterial infections and mycoses 01 natural sciences Biochemistry Trimethoprim female genital diseases and pregnancy complications 0104 chemical sciences 3. Good health 010404 medicinal & biomolecular chemistry Enzyme chemistry Drug Discovery medicine Trimethoprim Resistance heterocyclic compounds human activities medicine.drug |
| Zdroj: | ACS Med Chem Lett |
| ISSN: | 1948-5875 |
| DOI: | 10.1021/acsmedchemlett.0c00393 |
| Popis: | [Image: see text] Trimethoprim (TMP) is widely used to treat infections in humans and in livestock, accelerating the incidence of TMP resistance. The emergent and largely untracked type II dihydrofolate reductases (DfrBs) are intrinsically TMP-resistant plasmid-borne Dfrs that are structurally and evolutionarily unrelated to chromosomal Dfrs. We report kinetic characterization of the known DfrB family members. Their kinetic constants are conserved and all are poorly inhibited by TMP, consistent with TMP resistance. We investigate their inhibition with known and novel bisubstrate inhibitors of 6-hydroxymethyl-7,8-dihydropterin pyrophosphokinase (HPPK). Importantly, all are inhibited by the HPPK inhibitors, making these molecules dual-target inhibitors of two folate pathway enzymes that are strictly microbial. |
| Databáze: | OpenAIRE |
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