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

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 o...

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Autores principales: Jorba, Marta, Pedrola, Marina, Ghashghaei, Ouldouz, Herráez, Rocío, Campos-Vicens, Lluis, Luque, Franciso Javier, Lavilla, Rodolfo, Viñas, Miguel
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8231229/
https://www.ncbi.nlm.nih.gov/pubmed/34204647
http://dx.doi.org/10.3390/antibiotics10060709
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author Jorba, Marta
Pedrola, Marina
Ghashghaei, Ouldouz
Herráez, Rocío
Campos-Vicens, Lluis
Luque, Franciso Javier
Lavilla, Rodolfo
Viñas, Miguel
author_facet Jorba, Marta
Pedrola, Marina
Ghashghaei, Ouldouz
Herráez, Rocío
Campos-Vicens, Lluis
Luque, Franciso Javier
Lavilla, Rodolfo
Viñas, Miguel
author_sort Jorba, Marta
collection PubMed
description 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.
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spelling pubmed-82312292021-06-26 New Trimethoprim-Like Molecules: Bacteriological Evaluation and Insights into Their Action Jorba, Marta Pedrola, Marina Ghashghaei, Ouldouz Herráez, Rocío Campos-Vicens, Lluis Luque, Franciso Javier Lavilla, Rodolfo Viñas, Miguel Antibiotics (Basel) Article 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. MDPI 2021-06-12 /pmc/articles/PMC8231229/ /pubmed/34204647 http://dx.doi.org/10.3390/antibiotics10060709 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Jorba, Marta
Pedrola, Marina
Ghashghaei, Ouldouz
Herráez, Rocío
Campos-Vicens, Lluis
Luque, Franciso Javier
Lavilla, Rodolfo
Viñas, Miguel
New Trimethoprim-Like Molecules: Bacteriological Evaluation and Insights into Their Action
title New Trimethoprim-Like Molecules: Bacteriological Evaluation and Insights into Their Action
title_full New Trimethoprim-Like Molecules: Bacteriological Evaluation and Insights into Their Action
title_fullStr New Trimethoprim-Like Molecules: Bacteriological Evaluation and Insights into Their Action
title_full_unstemmed New Trimethoprim-Like Molecules: Bacteriological Evaluation and Insights into Their Action
title_short New Trimethoprim-Like Molecules: Bacteriological Evaluation and Insights into Their Action
title_sort new trimethoprim-like molecules: bacteriological evaluation and insights into their action
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8231229/
https://www.ncbi.nlm.nih.gov/pubmed/34204647
http://dx.doi.org/10.3390/antibiotics10060709
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