(500.9) A Small-molecule Inhibitor VM17 Targeting a Transcriptional Regulator HlyU Attenuates the Virulence of Vibrio vulnificus

Poster Board Number: A225

Sang Ho Choi (Seoul National University)

Vibrio vulnificus is a causative agent of food-borne diseases including gastroenteritis and life-threatening septicemia. Exotoxins such as a multifunctional-autoprocessing repeats-in-toxin (MARTX) toxin, a hemolysin, and a phospholipase A2 encoded by rtxA, vvhA, and plpA genes, respectively, are essential virulence factors. Interestingly, the expression of rtxA, vvhA, and plpA is activated by a transcriptional regulator HlyU. Therefore, HlyU can be an attractive target to control the virulence of V. vulnificus. We performed a high-throughput screening of 8,364 molecules at 20 µM using Escherichia coli containing HlyU-expressing and HlyU-dependent reporter plasmids. A small molecule VM17 exhibiting the most effective HlyU-inhibiting activity was selected and verified. VM17 did not affect the cellular HlyU levels, indicating that VM17 could inhibit the HlyU activity. The expression of rtxA, vvhA, and plpA in the wild type was significantly reduced in the presence of 20 µM of VM17. Consistent with this, VM17 enhanced the survival rate of the mice infected with V. vulnificus, indicating that the small molecule inhibits the virulence of V. vulnificus in vitro and in vivo. In conclusion, the combined results suggested that VM17 could be a novel lead compound to attenuate the virulence of V. vulnificus with a low probability of developing resistance.

This work was supported by the National Research Foundation of Korea, funded by the Ministry of Science, ICT, and Future Planning (2017R1E1A1A01074639).