Dataset Information

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

ABSTRACT: 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.

SUBMITTER: Jorba M

PROVIDER: S-EPMC8231229 | biostudies-literature | 2021 Jun

REPOSITORIES: biostudies-literature

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

Jorba Marta M Pedrola Marina M Ghashghaei Ouldouz O Herráez Rocío R Campos-Vicens Lluis L Luque Franciso Javier FJ Lavilla Rodolfo R Viñas Miguel M

Antibiotics (Basel, Switzerland) 20210612 6

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 ...[more]

PMID: 34204647

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Project description:Sulfamethoxazole (SMX) and trimethoprim (TRIM) are two of the most used antibiotics in the last 50 years, to prevent and treat bacterial infections; however, the available literature about toxicity to non-target organisms is quite discrepant and incomplete. This study aims to assess the SMX and TRIM ecotoxicological effects in standard species: Aliivibrio fischeri (bioluminescence inhibition), Escherichia coli ATCC 25922 (growth inhibition), Lemna minor (growth inhibition and biochemical biomarkers), Daphnia magna (immobilization/mortality, life history traits, and biochemical biomarkers), and Danio rerio (survival, hatching, abnormalities, and biochemical biomarkers). The species tested showed different acute sensitivities to SMX (A. fischeri < D. magna < E. coli < L. minor) and TRIM (L. minor < A. fischeri < D. magna < E. coli). Overall, TRIM reveals less toxicity than SMX, except for E. coli (Ecotoxicological approach based on Antimicrobial Susceptibility Testing - EcoAST procedure). Both antibiotics affect individually (e.g., growth and survival) and sub-individually (e.g., antioxidant defenses) L. minor, D. magna, and D. rerio. This study allowed us to generate relevant data and fill gaps in the literature regarding the effects of SMX and TRIM in aquatic organisms. The here-obtained results can be used to (i) complete and re-evaluate the Safety Data Sheet to improve the assessment of environmental safety and management of national and international entities; (ii) clarify the environmental risks of these antibiotics in aquatic ecosystems reinforcing the inclusion in the 4th Watch List of priority substances to be monitored in whole inland waters by the Water Framework Directive; and (iii) combat the development of antimicrobial resistance, as well as supporting the definition of environmental measurements in the context of European One Health Action Plan. However, it is essential to continue studying these antibiotics to better understand their toxicity at ecologically relevant concentrations and their long-term effects under different climatic change scenarios.

Dataset Information

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

Publications

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

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