4.6 Article

New Trimethoprim-Like Molecules: Bacteriological Evaluation and Insights into Their Action

期刊

ANTIBIOTICS-BASEL
卷 10, 期 6, 页码 -

出版社

MDPI
DOI: 10.3390/antibiotics10060709

关键词

trimethoprim; multidrug-resistant (MDR) bacteria; mechanisms of action; dihydrofolate reductase

资金

  1. Marato TV3 Foundation
  2. Ministerio de Ciencia e Innovacion-Spain [PID2019-107991RB-I00]
  3. Generalitat de Catalunya [2017SGR1746]
  4. Consorci de Serveis Universitaris de Catalunya

向作者/读者索取更多资源

This study investigates the antimicrobial properties of two trimethoprim-like molecules in combination with sulfamethoxazole, showing significant activity and synergistic effects with colistin. The mechanism of action may involve alterations in bacterial growth kinetics and increased antibiotic entry while reducing efflux pump activity. The interactions between the target enzyme, coenzyme, and studied molecules were explored using enzymology tools and computational chemistry, and a docking-based model was proposed.
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 beta-naphthylamide (PA beta N) 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.

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