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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| Format: | Article |
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MDPI AG
2021-06-01
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| Series: | Pharmaceuticals |
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| Online Access: | https://www.mdpi.com/1424-8247/14/6/572 |
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| author | Fernando Durães Andreia Palmeira Bárbara Cruz Joana Freitas-Silva Nikoletta Szemerédi Luís Gales Paulo Martins da Costa Fernando Remião Renata Silva Madalena Pinto Gabriella Spengler Emília Sousa |
| author_facet | Fernando Durães Andreia Palmeira Bárbara Cruz Joana Freitas-Silva Nikoletta Szemerédi Luís Gales Paulo Martins da Costa Fernando Remião Renata Silva Madalena Pinto Gabriella Spengler Emília Sousa |
| author_sort | Fernando Durães |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-03-10T10:22:33Z |
| format | Article |
| id | doaj.art-7e42754966b94444b1c0227c2486c774 |
| institution | Directory Open Access Journal |
| issn | 1424-8247 |
| language | English |
| last_indexed | 2024-03-10T10:22:33Z |
| publishDate | 2021-06-01 |
| publisher | MDPI AG |
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| series | Pharmaceuticals |
| spelling | doaj.art-7e42754966b94444b1c0227c2486c7742023-11-22T00:16:29ZengMDPI AGPharmaceuticals1424-82472021-06-0114657210.3390/ph14060572Antimicrobial Activity of a Library of Thioxanthones and Their Potential as Efflux Pump InhibitorsFernando Durães0Andreia Palmeira1Bárbara Cruz2Joana Freitas-Silva3Nikoletta Szemerédi4Luís Gales5Paulo Martins da Costa6Fernando Remião7Renata Silva8Madalena Pinto9Gabriella Spengler10Emília Sousa11Laboratory of Organic and Pharmaceutical Chemistry, Department of Chemical Sciences, Faculty of Pharmacy, University of Porto, Rua de Jorge Viterbo Ferreira, 228, 4050-313 Porto, PortugalLaboratory of Organic and Pharmaceutical Chemistry, Department of Chemical Sciences, Faculty of Pharmacy, University of Porto, Rua de Jorge Viterbo Ferreira, 228, 4050-313 Porto, PortugalUCIBIO-REQUIMTE, Laboratory of Toxicology, Faculty of Pharmacy, University of Porto, Rua de Jorge Viterbo Ferreira 228, 4050-313 Porto, PortugalCIIMAR-Interdisciplinary Centre of Marine and Environmental Research, University of Porto, Novo Edifício do Terminal de Cruzeiros do Porto de Leixões, Avenida General Norton de Matos, S/N, 4450-208 Matosinhos, PortugalDepartment of Medical Microbiology, Albert Szent-Györgyi Health Center and Faculty of Medicine, University of Szeged, Semmelweis utca 6, 6725 Szeged, HungaryDepartment of Molecular Biology, ICBAS–Instituto de Ciências Biomédicas Abel Salazar, University of Porto, Rua de Jorge Viterbo Ferreira 228, 4050-313 Porto, PortugalCIIMAR-Interdisciplinary Centre of Marine and Environmental Research, University of Porto, Novo Edifício do Terminal de Cruzeiros do Porto de Leixões, Avenida General Norton de Matos, S/N, 4450-208 Matosinhos, PortugalUCIBIO-REQUIMTE, Laboratory of Toxicology, Faculty of Pharmacy, University of Porto, Rua de Jorge Viterbo Ferreira 228, 4050-313 Porto, PortugalUCIBIO-REQUIMTE, Laboratory of Toxicology, Faculty of Pharmacy, University of Porto, Rua de Jorge Viterbo Ferreira 228, 4050-313 Porto, PortugalLaboratory of Organic and Pharmaceutical Chemistry, Department of Chemical Sciences, Faculty of Pharmacy, University of Porto, Rua de Jorge Viterbo Ferreira, 228, 4050-313 Porto, PortugalDepartment of Medical Microbiology, Albert Szent-Györgyi Health Center and Faculty of Medicine, University of Szeged, Semmelweis utca 6, 6725 Szeged, HungaryLaboratory of Organic and Pharmaceutical Chemistry, Department of Chemical Sciences, Faculty of Pharmacy, University of Porto, Rua de Jorge Viterbo Ferreira, 228, 4050-313 Porto, PortugalThe 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.https://www.mdpi.com/1424-8247/14/6/572thioxanthonesantimicrobial resistanceefflux pumpsbiofilmquorum-sensing |
| spellingShingle | Fernando Durães Andreia Palmeira Bárbara Cruz Joana Freitas-Silva Nikoletta Szemerédi Luís Gales Paulo Martins da Costa Fernando Remião Renata Silva Madalena Pinto Gabriella Spengler Emília Sousa Antimicrobial Activity of a Library of Thioxanthones and Their Potential as Efflux Pump Inhibitors Pharmaceuticals thioxanthones antimicrobial resistance efflux pumps biofilm quorum-sensing |
| 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 | thioxanthones antimicrobial resistance efflux pumps biofilm quorum-sensing |
| url | https://www.mdpi.com/1424-8247/14/6/572 |
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