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Article

Benzydamine Reverses TMexCD-TOprJ-Mediated High-Level Tigecycline Resistance in Gram-Negative Bacteria

by 1, 1, 1, 1, 1,2,* and 1,2,3,*
1
College of Veterinary Medicine, Yangzhou University, Yangzhou 225009, China
2
Jiangsu Co-Innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Joint International Research Laboratory of Agriculture and Agri-Product Safety, The Ministry of Education of China, Yangzhou University, Yangzhou 225009, China
3
Institute of Comparative Medicine, Yangzhou University, Yangzhou 225009, China
*
Authors to whom correspondence should be addressed.
Academic Editor: Michaela Wenzel
Pharmaceuticals 2021, 14(9), 907; https://doi.org/10.3390/ph14090907
Received: 18 August 2021 / Accepted: 2 September 2021 / Published: 7 September 2021
(This article belongs to the Special Issue Mechanisms of Antibiotic Action and Resistance)
Recently, a novel efflux pump gene cluster called tmexCD1-toprJ1 and its variants have been identified, which undermine the antibacterial activity of tigecycline, one of the last remaining options effective against multidrug-resistant (MDR) Gram-negative bacteria. Herein, we report the potent synergistic effect of the non-steroidal anti-inflammatory drug benzydamine in combination with tigecycline at sub-inhibitory concentrations against various temxCD-toprJ-positive Gram-negative pathogens. The combination of benzydamine and tigecycline killed all drug-resistant pathogens during 24 h of incubation. In addition, the evolution of tigecycline resistance was significantly suppressed in the presence of benzydamine. Studies on the mechanisms of synergism showed that benzydamine disrupted the bacterial proton motive force and the functionality of this kind of novel plasmid-encoded resistance-nodulation-division efflux pump, thereby promoting the intracellular accumulation of tigecycline. Most importantly, the combination therapy of benzydamine and tigecycline effectively improved the survival of Galleria mellonella larvae compared to tigecycline monotherapy. Our findings provide a promising drug combination therapeutic strategy for combating superbugs carrying the tmexCD-toprJ gene. View Full-Text
Keywords: tigecycline resistance; efflux pump; tmexCD-toprJ; benzydamine; Gram-negative bacteria tigecycline resistance; efflux pump; tmexCD-toprJ; benzydamine; Gram-negative bacteria
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MDPI and ACS Style

Tong, Z.; Xu, T.; Deng, T.; Shi, J.; Wang, Z.; Liu, Y. Benzydamine Reverses TMexCD-TOprJ-Mediated High-Level Tigecycline Resistance in Gram-Negative Bacteria. Pharmaceuticals 2021, 14, 907. https://doi.org/10.3390/ph14090907

AMA Style

Tong Z, Xu T, Deng T, Shi J, Wang Z, Liu Y. Benzydamine Reverses TMexCD-TOprJ-Mediated High-Level Tigecycline Resistance in Gram-Negative Bacteria. Pharmaceuticals. 2021; 14(9):907. https://doi.org/10.3390/ph14090907

Chicago/Turabian Style

Tong, Ziwen, Tianqi Xu, Tian Deng, Jingru Shi, Zhiqiang Wang, and Yuan Liu. 2021. "Benzydamine Reverses TMexCD-TOprJ-Mediated High-Level Tigecycline Resistance in Gram-Negative Bacteria" Pharmaceuticals 14, no. 9: 907. https://doi.org/10.3390/ph14090907

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