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Reversion of antibiotic resistance in drug-resistant bacteria using non-steroidal anti-inflammatory drug benzydamine

View ORCID ProfileYuan Liu, Ziwen Tong, Jingru Shi, Tian Deng, Ruichao Li, Xia Xiao, Zhiqiang Wang
doi: https://doi.org/10.1101/2021.05.07.443075
Yuan Liu
aCollege of Veterinary Medicine, Yangzhou University, Yangzhou 225009, China
bInstitute of Comparative Medicine, Yangzhou University, Yangzhou 225009, China
cJiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou University, Yangzhou 225009, China
dJoint International Research Laboratory of Agriculture and Agri-Product Safety, the Ministry of Education of China, Yangzhou University, Yangzhou 225009, China
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  • For correspondence: zqwang@yzu.edu.cn liuyuan2018@yzu.edu.cn
Ziwen Tong
aCollege of Veterinary Medicine, Yangzhou University, Yangzhou 225009, China
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Jingru Shi
aCollege of Veterinary Medicine, Yangzhou University, Yangzhou 225009, China
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Tian Deng
aCollege of Veterinary Medicine, Yangzhou University, Yangzhou 225009, China
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Ruichao Li
aCollege of Veterinary Medicine, Yangzhou University, Yangzhou 225009, China
bInstitute of Comparative Medicine, Yangzhou University, Yangzhou 225009, China
cJiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou University, Yangzhou 225009, China
dJoint International Research Laboratory of Agriculture and Agri-Product Safety, the Ministry of Education of China, Yangzhou University, Yangzhou 225009, China
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Xia Xiao
aCollege of Veterinary Medicine, Yangzhou University, Yangzhou 225009, China
cJiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou University, Yangzhou 225009, China
dJoint International Research Laboratory of Agriculture and Agri-Product Safety, the Ministry of Education of China, Yangzhou University, Yangzhou 225009, China
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Zhiqiang Wang
aCollege of Veterinary Medicine, Yangzhou University, Yangzhou 225009, China
cJiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou University, Yangzhou 225009, China
dJoint International Research Laboratory of Agriculture and Agri-Product Safety, the Ministry of Education of China, Yangzhou University, Yangzhou 225009, China
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  • For correspondence: zqwang@yzu.edu.cn liuyuan2018@yzu.edu.cn
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Abstract

Antimicrobial resistance has been a growing concern that gradually undermines our tradition treatment regimen. The fact that few antibacterial drugs with new scaffolds or targets have been approved in the past two decades aggravates this crisis. Repurposing previously approved drugs as potent antibiotic adjuvants offers a cost-effective strategy to mitigate the development of resistance and tackle the increasing infections by multidrug-resistant (MDR) bacteria. Herein, we found that benzydamine, a widely used non-steroidal anti-inflammatory drug in clinic, remarkably potentiated broad-spectrum antibiotic-tetracyclines activity against a panel of clinical important resistant pathogens, including MRSA, VRE, MCRPEC and tet(X)-positive Gram-negative bacteria. Further mechanistically experiments showed that benzydamine dissipated membrane potential (ΔΨ) in both Gram-positive and negative bacteria, which in turn upregulated the transmembrane proton gradient (ΔpH) and promoted the uptake of tetracyclines. Additionally, benzydamine exacerbated the oxidative stress by triggering the production of ROS and suppressing GAD system-mediated oxidative defensive. This mode of action explains the great bactericidal activity of the doxycycline-benzydamine combination against different metabolic states of bacteria including persister cells. As a proof-of-concept, the in vivo efficacy of this combination therapy was evidenced in multiple animal infection models. These findings revealed that benzydamine is a promising tetracycline antibiotics adjuvant and has the potential to address life-threatening infections by MDR bacteria.

Competing Interest Statement

The authors have declared no competing interest.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license.
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Posted May 07, 2021.
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Reversion of antibiotic resistance in drug-resistant bacteria using non-steroidal anti-inflammatory drug benzydamine
Yuan Liu, Ziwen Tong, Jingru Shi, Tian Deng, Ruichao Li, Xia Xiao, Zhiqiang Wang
bioRxiv 2021.05.07.443075; doi: https://doi.org/10.1101/2021.05.07.443075
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Reversion of antibiotic resistance in drug-resistant bacteria using non-steroidal anti-inflammatory drug benzydamine
Yuan Liu, Ziwen Tong, Jingru Shi, Tian Deng, Ruichao Li, Xia Xiao, Zhiqiang Wang
bioRxiv 2021.05.07.443075; doi: https://doi.org/10.1101/2021.05.07.443075

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