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Title 

Small-molecule inhibitor of HlyU attenuates virulence of Vibrio species

Authors 

Z W LeeByoung Sik KimK K JangY J BangS KimN C HaY H JungH J LeeH J HanJ S KimJ KimP K SahuL S JeongMyung Hee KimS H Choi

Publisher 

Nature Publishing Group

Issue Date 

2019

Citation 

Scientific Reports

Abstract 

Increasing antibiotic resistance has led to the development of new strategies to combat bacterial infection. Anti-virulence strategies that impair virulence of bacterial pathogens are one of the novel approaches with less selective pressure for developing resistance than traditional strategies that impede viability. In this study, a small molecule CM14 [N-(4-oxo-4H-thieno[3,4-c]chromen-3-yl)-3-phenylprop-2-ynamide] that inhibits the activity of HlyU, a transcriptional regulator essential for the virulence of the fulminating human pathogen Vibrio vulnificus, has been identified. Without affecting bacterial growth or triggering the host cell death, CM14 reduces HlyU-dependent expression of virulence genes in V. vulnificus. In addition to the decreased hemolysis of human erythrocytes, CM14 impedes host cell rounding and lysis caused by V. vulnificus. Notably, CM14 significantly enhances survival of mice infected with V. vulnificus by alleviating hepatic and renal dysfunction and systemic inflammation. Biochemical, mass spectrometric, and mutational analyses revealed that CM14 inhibits HlyU from binding to target DNA by covalently modifying Cys30. Remarkably, CM14 decreases the expression of various virulence genes of other Vibrio species and thus attenuates their virulence phenotypes. Together, this molecule could be an anti-virulence agent against HlyU-harboring Vibrio species with a low selective pressure for the emergence of resistance.

URI 

https://doi.org/10.1038/s41598-019-39554-y

ISSN 

2045-2322

Appears in Collections

1. Journal Articles > Journal Articles

Registered Date

2019-05-02


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