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Antimicrobial Activity of a Library of Thioxanthones and Their Potential as Efflux Pump Inhibitors

The overexpression of efflux pumps is one of the causes of multidrug resistance, which leads to the inefficacy of drugs. This plays a pivotal role in antimicrobial resistance, and the most notable pumps are the AcrAB-TolC system (AcrB belongs to the resistance-nodulation-division family) and the Nor...

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Autores principales: Durães, Fernando, Palmeira, Andreia, Cruz, Bárbara, Freitas-Silva, Joana, Szemerédi, Nikoletta, Gales, Luís, da Costa, Paulo Martins, Remião, Fernando, Silva, Renata, Pinto, Madalena, Spengler, Gabriella, Sousa, Emília
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8232621/
https://www.ncbi.nlm.nih.gov/pubmed/34203998
http://dx.doi.org/10.3390/ph14060572
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author Durães, Fernando
Palmeira, Andreia
Cruz, Bárbara
Freitas-Silva, Joana
Szemerédi, Nikoletta
Gales, Luís
da Costa, Paulo Martins
Remião, Fernando
Silva, Renata
Pinto, Madalena
Spengler, Gabriella
Sousa, Emília
author_facet Durães, Fernando
Palmeira, Andreia
Cruz, Bárbara
Freitas-Silva, Joana
Szemerédi, Nikoletta
Gales, Luís
da Costa, Paulo Martins
Remião, Fernando
Silva, Renata
Pinto, Madalena
Spengler, Gabriella
Sousa, Emília
author_sort Durães, Fernando
collection PubMed
description The overexpression of efflux pumps is one of the causes of multidrug resistance, which leads to the inefficacy of drugs. This plays a pivotal role in antimicrobial resistance, and the most notable pumps are the AcrAB-TolC system (AcrB belongs to the resistance-nodulation-division family) and the NorA, from the major facilitator superfamily. In bacteria, these structures can also favor virulence and adaptation mechanisms, such as quorum-sensing and the formation of biofilm. In this study, the design and synthesis of a library of thioxanthones as potential efflux pump inhibitors are described. The thioxanthone derivatives were investigated for their antibacterial activity and inhibition of efflux pumps, biofilm formation, and quorum-sensing. The compounds were also studied for their potential to interact with P-glycoprotein (P-gp, ABCB1), an efflux pump present in mammalian cells, and for their cytotoxicity in both mouse fibroblasts and human Caco-2 cells. The results concerning the real-time ethidium bromide accumulation may suggest a potential bacterial efflux pump inhibition, which has not yet been reported for thioxanthones. Moreover, in vitro studies in human cells demonstrated a lack of cytotoxicity for concentrations up to 20 µM in Caco-2 cells, with some derivatives also showing potential for P-gp modulation.
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spelling pubmed-82326212021-06-26 Antimicrobial Activity of a Library of Thioxanthones and Their Potential as Efflux Pump Inhibitors Durães, Fernando Palmeira, Andreia Cruz, Bárbara Freitas-Silva, Joana Szemerédi, Nikoletta Gales, Luís da Costa, Paulo Martins Remião, Fernando Silva, Renata Pinto, Madalena Spengler, Gabriella Sousa, Emília Pharmaceuticals (Basel) Article The overexpression of efflux pumps is one of the causes of multidrug resistance, which leads to the inefficacy of drugs. This plays a pivotal role in antimicrobial resistance, and the most notable pumps are the AcrAB-TolC system (AcrB belongs to the resistance-nodulation-division family) and the NorA, from the major facilitator superfamily. In bacteria, these structures can also favor virulence and adaptation mechanisms, such as quorum-sensing and the formation of biofilm. In this study, the design and synthesis of a library of thioxanthones as potential efflux pump inhibitors are described. The thioxanthone derivatives were investigated for their antibacterial activity and inhibition of efflux pumps, biofilm formation, and quorum-sensing. The compounds were also studied for their potential to interact with P-glycoprotein (P-gp, ABCB1), an efflux pump present in mammalian cells, and for their cytotoxicity in both mouse fibroblasts and human Caco-2 cells. The results concerning the real-time ethidium bromide accumulation may suggest a potential bacterial efflux pump inhibition, which has not yet been reported for thioxanthones. Moreover, in vitro studies in human cells demonstrated a lack of cytotoxicity for concentrations up to 20 µM in Caco-2 cells, with some derivatives also showing potential for P-gp modulation. MDPI 2021-06-15 /pmc/articles/PMC8232621/ /pubmed/34203998 http://dx.doi.org/10.3390/ph14060572 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
Durães, Fernando
Palmeira, Andreia
Cruz, Bárbara
Freitas-Silva, Joana
Szemerédi, Nikoletta
Gales, Luís
da Costa, Paulo Martins
Remião, Fernando
Silva, Renata
Pinto, Madalena
Spengler, Gabriella
Sousa, Emília
Antimicrobial Activity of a Library of Thioxanthones and Their Potential as Efflux Pump Inhibitors
title Antimicrobial Activity of a Library of Thioxanthones and Their Potential as Efflux Pump Inhibitors
title_full Antimicrobial Activity of a Library of Thioxanthones and Their Potential as Efflux Pump Inhibitors
title_fullStr Antimicrobial Activity of a Library of Thioxanthones and Their Potential as Efflux Pump Inhibitors
title_full_unstemmed Antimicrobial Activity of a Library of Thioxanthones and Their Potential as Efflux Pump Inhibitors
title_short Antimicrobial Activity of a Library of Thioxanthones and Their Potential as Efflux Pump Inhibitors
title_sort antimicrobial activity of a library of thioxanthones and their potential as efflux pump inhibitors
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8232621/
https://www.ncbi.nlm.nih.gov/pubmed/34203998
http://dx.doi.org/10.3390/ph14060572
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