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Molecules 2018, 23(6), 1492; https://doi.org/10.3390/molecules23061492

Identification of 2′,4′-Dihydroxychalcone as an Antivirulence Agent Targeting HlyU, a Master Virulence Regulator in Vibrio vulnificus

Department of Molecular Cell Biology, School of Medicine, Samsung Medical Center, Sungkyunkwan University, Suwon 16419, Korea
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Received: 9 May 2018 / Revised: 14 June 2018 / Accepted: 19 June 2018 / Published: 20 June 2018
(This article belongs to the Section Chemical Biology)
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Abstract

The emergence of antimicrobial resistance and rapid acclimation allows Vibrio vulnificus to rapidly propagate in the host. This problematic pathological scenario can be circumvented by employing an antivirulence strategy, treating Vibrio infections without hindering the bacterial growth. We developed a genome-integrated orthogonal inhibitor screening platform in E. coli to identify antivirulence agents targeting a master virulence regulator of V. vulnificus. We identified 2′,4′-dihydroxychalcone (DHC) from the natural compound library and verified that it decreases the expression of the major toxin network which is equivalent to the ∆hlyU deletion mutant. 2′,4′-DHC also reduced the hemolytic activity of V. vulnificus which was tested as an example of virulence phenotype. The electrophoretic mobility shift assay confirmed that 2′,4′-DHC specifically targeted HlyU and inhibited its binding to PrtxA1 promoter. Under in vivo conditions, a single dose of 2′,4′-DHC protected ~50% wax-worm larvae from V. vulnificus infection at a non-toxic concentration to both V. vulnificus and wax-worm larvae. In the current study, we demonstrated that an orthogonal reporter system is suitable for the identification of antivirulence compounds with accuracy, and identified 2′,4′-DHC as a potent antivirulence agent that specifically targets the HlyU virulence transcriptional regulator and significantly reduces the virulence and infection potential of V. vulnificus. View Full-Text
Keywords: HlyU inhibitor; virulence factors; toxin-network; Vibrio vulnificus; 2′,4′-dihydroxychalcone; foodborne infectious disease; Galleria mellonella infection model, orthogonal screening reporter platform HlyU inhibitor; virulence factors; toxin-network; Vibrio vulnificus; 2′,4′-dihydroxychalcone; foodborne infectious disease; Galleria mellonella infection model, orthogonal screening reporter platform
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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Imdad, S.; Batool, N.; Pradhan, S.; Chaurasia, A.K.; Kim, K.K. Identification of 2′,4′-Dihydroxychalcone as an Antivirulence Agent Targeting HlyU, a Master Virulence Regulator in Vibrio vulnificus. Molecules 2018, 23, 1492.

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