Small-molecule inhibitor of Vibrio cholerae virulence and intestinal colonization

Speaker : 李璟采                                      place : Room 601

Commentator : 劉清泉 醫師                            time : 15:00~16:00

Cholera is a dramatic and life-threatening disease characterized by profuse watery diarrhea that leads to massive dehydration and frequently death in untreated patients. The diease is caused by the Gram-negative bacterium V. cholerae, which elaborates two major virulence factors, cholera toxin (CT) and the toxin coregulated pilus (TCP)¹. In this study, the authors found a new class of antibiotics for V. cholerae by targeting the regulation of its virulence factors². They constructed a screening strain from the classical biotype strain O395. This strain carries a chromosomally integrated tetracycline resistance gene (tetA) controlled by the cholera toxin (ctx) promoter. With this strain, they identified a small molecule, virstatin, which inhibited the cholera toxin promoter (ctx) activity. They found that virstatin did not inhibit the growth of V. cholerae, but could inhibit the expression of major subunit of TCP. They further examined the effect of virstatin on the transcription of upstream regulators of CT and TCP. One of these regulators, ToxT that activates multiple virulence genes including ctxAB and tcp, was not effect by virstatin on the transcriptional level. However, the post-translational level of ToxT was inhibited by virstatin, suggesting that the inhibition is post-translational. They also examined the effect of virstatin on the colonization of infant mice by V. cholerae strains in a TCP-dependent versus-independent manner. The competition experiments that compared the relative ratios of a TCP-dependent strain and a TCP-independent strain showed that, in contract to the TCP-independent strain, very few colonies of the TCP-dependent strain could be counted when treated with virstatin. These data complement prior observation on the requirement of early in vivo virulence expression. Conclusively, the identification of inhibitors of virulence represents a path to anti-infective discovery that is quite different from previous antibiotics that target only bacterial processes that are essential both in vivo and in vitro.

References:

1.     M. K. Waldor, J. J. Mekalanos, in Enteric Infections and Immunity, pp. 37-55, 1996

2.     D. T. Hung, E. A. Shakhnovich, E. Pierson, J. J. Mekalanos, Small-molecule inhibitor of Vibrio cholerae virulence and intestinal colonization. Science 310: 670-674 (2005)