New Trimethoprim-Like Molecules: Bacteriological Evaluation and Insights into Their Action
| Autor: | Franciso Javier Luque, Lluis Campos-Vicens, Ouldouz Ghashghaei, Miguel Viñas, Rodolfo Lavilla, Marta Jorba, Rocío Herráez, Marina Pedrola |
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| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Microbiology (medical) 030106 microbiology Antibiòtics RM1-950 Biochemistry Microbiology Bacteris Cofactor Article 03 medical and health sciences chemistry.chemical_compound dihydrofolate reductase Antibiotics Dihydrofolate reductase multidrug-resistant (MDR) bacteria medicine Pharmacology (medical) trimethoprim General Pharmacology Toxicology and Pharmaceutics Resistència als medicaments chemistry.chemical_classification biology Bacteria Antimicrobial mechanisms of action 030104 developmental biology Infectious Diseases Enzyme chemistry Docking (molecular) Drug resistance biology.protein Colistin Efflux Therapeutics. Pharmacology Nicotinamide adenine dinucleotide phosphate medicine.drug |
| Zdroj: | Dipòsit Digital de la UB Universidad de Barcelona Antibiotics Volume 10 Issue 6 Antibiotics, Vol 10, Iss 709, p 709 (2021) |
| ISSN: | 2079-6382 |
| Popis: | This work reports a detailed characterization of the antimicrobial profile of two trimethoprim-like molecules (compounds 1a and 1b) identified in previous studies. Both molecules displayed remarkable antimicrobial activity, particularly when combined with sulfamethoxazole. In disk diffusion assays on Petri dishes, compounds 1a and 1b showed synergistic effects with colistin. Specifically, in combinations with low concentrations of colistin, very large increases in the activities of compounds 1a and 1b were determined, as demonstrated by alterations in the kinetics of bacterial growth despite only slight changes in the fractional inhibitory concentration index. The effect of colistin may be to increase the rate of antibiotic entry while reducing efflux pump activity. Compounds 1a and 1b were susceptible to extrusion by efflux pumps, whereas the inhibitor phenylalanine arginyl β-naphthylamide (PAβN) exerted effects similar to those of colistin. The interactions between the target enzyme (dihydrofolate reductase), the coenzyme nicotinamide adenine dinucleotide phosphate (NADPH), and the studied molecules were explored using enzymology tools and computational chemistry. A model based on docking results is reported. |
| Databáze: | OpenAIRE |
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