Artesunate, EDTA, and colistin work synergistically against MCR-negative and -positive colistin-resistant Salmonella
Discovering new strategies to combat the multidrug-resistant bacteria constitutes a major medical challenge of our time. Previously, artesunate (AS) has been reported to exert antibacterial enhancement activity in combination with β-lactam antibiotics via inhibition of the efflux pump AcrB. However,...
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eLife Sciences Publications Ltd
2025-02-01
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| Online Access: | https://elifesciences.org/articles/99130 |
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| author | Yajun Zhai Peiyi Liu Xueqin Hu Changjian Fan Xiaodie Cui Qibiao He Dandan He Xiaoyuan Ma Gongzheng Hu |
| author_facet | Yajun Zhai Peiyi Liu Xueqin Hu Changjian Fan Xiaodie Cui Qibiao He Dandan He Xiaoyuan Ma Gongzheng Hu |
| author_sort | Yajun Zhai |
| collection | DOAJ |
| description | Discovering new strategies to combat the multidrug-resistant bacteria constitutes a major medical challenge of our time. Previously, artesunate (AS) has been reported to exert antibacterial enhancement activity in combination with β-lactam antibiotics via inhibition of the efflux pump AcrB. However, combination of AS and colistin (COL) revealed a weak synergistic effect against a limited number of strains, and few studies have further explored its possible mechanism of synergistic action. In this article, we found that AS and EDTA could strikingly enhance the antibacterial effects of COL against mcr-1- and mcr-1+ Salmonella strains either in vitro or in vivo, when used in triple combination. The excellent bacteriostatic effect was primarily related to the increased cell membrane damage, accumulation of toxic compounds and inhibition of MCR-1. The potential binding sites of AS to MCR-1 (THR283, SER284, and TYR287) were critical for its inhibition of MCR-1 activity. Additionally, we also demonstrated that the CheA of chemosensory system and virulence-related protein SpvD were critical for the bacteriostatic synergistic effects of the triple combination. Selectively targeting CheA, SpvD, or MCR using the natural compound AS could be further investigated as an attractive strategy for the treatment of Salmonella infection. Collectively, our work opens new avenues toward the potentiation of COL and reveals an alternative drug combination strategy to overcome COL-resistant bacterial infections. |
| format | Article |
| id | doaj-art-e30ae56e1c714b1eb613f80753353cb6 |
| institution | Kabale University |
| issn | 2050-084X |
| language | English |
| publishDate | 2025-02-01 |
| publisher | eLife Sciences Publications Ltd |
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| spelling | doaj-art-e30ae56e1c714b1eb613f80753353cb62025-02-07T16:09:35ZengeLife Sciences Publications LtdeLife2050-084X2025-02-011310.7554/eLife.99130Artesunate, EDTA, and colistin work synergistically against MCR-negative and -positive colistin-resistant SalmonellaYajun Zhai0https://orcid.org/0009-0002-2218-4819Peiyi Liu1Xueqin Hu2Changjian Fan3Xiaodie Cui4Qibiao He5Dandan He6Xiaoyuan Ma7Gongzheng Hu8Department of Pharmacology and Toxicology, College of Veterinary Medicine, Henan Agricultural University, Zhengzhou, ChinaDepartment of Pharmacology and Toxicology, College of Veterinary Medicine, Henan Agricultural University, Zhengzhou, ChinaDepartment of Pharmacology and Toxicology, College of Veterinary Medicine, Henan Agricultural University, Zhengzhou, ChinaDepartment of Pharmacology and Toxicology, College of Veterinary Medicine, Henan Agricultural University, Zhengzhou, ChinaDepartment of Pharmacology and Toxicology, College of Veterinary Medicine, Henan Agricultural University, Zhengzhou, ChinaDepartment of Pharmacology and Toxicology, College of Veterinary Medicine, Henan Agricultural University, Zhengzhou, ChinaDepartment of Pharmacology and Toxicology, College of Veterinary Medicine, Henan Agricultural University, Zhengzhou, ChinaDepartment of Pharmacology and Toxicology, College of Veterinary Medicine, Henan Agricultural University, Zhengzhou, ChinaDepartment of Pharmacology and Toxicology, College of Veterinary Medicine, Henan Agricultural University, Zhengzhou, ChinaDiscovering new strategies to combat the multidrug-resistant bacteria constitutes a major medical challenge of our time. Previously, artesunate (AS) has been reported to exert antibacterial enhancement activity in combination with β-lactam antibiotics via inhibition of the efflux pump AcrB. However, combination of AS and colistin (COL) revealed a weak synergistic effect against a limited number of strains, and few studies have further explored its possible mechanism of synergistic action. In this article, we found that AS and EDTA could strikingly enhance the antibacterial effects of COL against mcr-1- and mcr-1+ Salmonella strains either in vitro or in vivo, when used in triple combination. The excellent bacteriostatic effect was primarily related to the increased cell membrane damage, accumulation of toxic compounds and inhibition of MCR-1. The potential binding sites of AS to MCR-1 (THR283, SER284, and TYR287) were critical for its inhibition of MCR-1 activity. Additionally, we also demonstrated that the CheA of chemosensory system and virulence-related protein SpvD were critical for the bacteriostatic synergistic effects of the triple combination. Selectively targeting CheA, SpvD, or MCR using the natural compound AS could be further investigated as an attractive strategy for the treatment of Salmonella infection. Collectively, our work opens new avenues toward the potentiation of COL and reveals an alternative drug combination strategy to overcome COL-resistant bacterial infections.https://elifesciences.org/articles/99130triple combinationcolistin resistantSalmonella |
| spellingShingle | Yajun Zhai Peiyi Liu Xueqin Hu Changjian Fan Xiaodie Cui Qibiao He Dandan He Xiaoyuan Ma Gongzheng Hu Artesunate, EDTA, and colistin work synergistically against MCR-negative and -positive colistin-resistant Salmonella eLife triple combination colistin resistant Salmonella |
| title | Artesunate, EDTA, and colistin work synergistically against MCR-negative and -positive colistin-resistant Salmonella |
| title_full | Artesunate, EDTA, and colistin work synergistically against MCR-negative and -positive colistin-resistant Salmonella |
| title_fullStr | Artesunate, EDTA, and colistin work synergistically against MCR-negative and -positive colistin-resistant Salmonella |
| title_full_unstemmed | Artesunate, EDTA, and colistin work synergistically against MCR-negative and -positive colistin-resistant Salmonella |
| title_short | Artesunate, EDTA, and colistin work synergistically against MCR-negative and -positive colistin-resistant Salmonella |
| title_sort | artesunate edta and colistin work synergistically against mcr negative and positive colistin resistant salmonella |
| topic | triple combination colistin resistant Salmonella |
| url | https://elifesciences.org/articles/99130 |
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