Canagliflozin Inhibited the Activity of Hemolysin and Reduced the Inflammatory Response Caused by Streptococcus suis
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Published:2023-08-22
Issue:17
Volume:24
Page:13074
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ISSN:1422-0067
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Container-title:International Journal of Molecular Sciences
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language:en
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Short-container-title:IJMS
Author:
Li Xiaodan12, Li Qingyuan2, Zhang Zhaoran2, Wang Chenchen2, Huo Xinyu2, Lai Hongjiang2, Lu Hao2, Lu Wenjia2, Qian Yulin2, Dong Wenqi2, Tan Chen2, Liu Manli1
Affiliation:
1. Hubei Biopesticide Engineering Research Centre, Wuhan 430000, China 2. College of Veterinary Medicine, Huazhong Agricultural University, Wuhan 430000, China
Abstract
Highly virulent Streptococcus suis (S. suis) infections can cause Streptococcal toxic shock-like syndrome (STSLS) in pigs and humans, in which an excessive inflammatory response causes severe damage. Hemolysin (SLY) is a major virulence factor of S. suis serotype 2 that produces pores in the target cell membrane, leading to cytoplasmic K+ efflux and activation of the NLRP3 inflammasome, ultimately causing STSLS. The critical aspect of hemolysin in the pathogenesis of S. suis type 2 makes it an attractive target for the development of innovative anti-virulence drugs. Here, we use the S. suis toxin protein (SLY) as a target for virtual screening. A compound called canagliflozin, a hypoglycemic agent, was identified through screening. Canagliflozin significantly inhibits the hemolytic activity of hemolysin. The results combined with molecular dynamics simulation, surface plasmon resonance, and nano differential scanning fluorimetry show that canagliflozin inhibits the hemolytic activity of SLY by binding to SLY. In addition, canagliflozin markedly reduced the release of SC19-induced inflammatory factors at the cellular level and in mice. Importantly, the combination of canagliflozin and ampicillin had a 90% success rate in mice, significantly greater than the therapeutic effect of ampicillin. The findings suggest that canagliflozin may be a promising new drug candidate for S. suis infections.
Funder
National Key Research and Development Program Hubei Provincial Science and Technology Major Project earmarked fund
Subject
Inorganic Chemistry,Organic Chemistry,Physical and Theoretical Chemistry,Computer Science Applications,Spectroscopy,Molecular Biology,General Medicine,Catalysis
Reference42 articles.
1. Global burden of bacterial antimicrobial resistance in 2019: A systematic analysis;Murray;Lancet,2022 2. Origins and evolution of antibiotic resistance;Davies;Microbiol. Mol. Biol. Rev.,2010 3. Assessment of the pathogenesis of Streptococcus suis type 2 infection in piglets for understanding streptococcal toxic shock-like syndrome, meningitis, and sequelae;Bi;Vet. Microbiol.,2014 4. Genome characteristics related to the virulence of Streptococcus suis in Swedish pigs;Werinder;Vet. Microbiol.,2023 5. Lin, L., Xu, L., Lv, W., Han, L., Xiang, Y., Fu, L., Jin, M., Zhou, R., Chen, H., and Zhang, A. (2019). An NLRP3 inflammasome-triggered cytokine storm contributes to Streptococcal toxic shock-like syndrome (STSLS). PLoS Pathog., 15.
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