Virstatin inhibits dimerization of the transcriptional activator ToxT.

Abstract:

:The development of antimicrobials is critical in this time of increasing antibiotic resistance of most clinically relevant bacteria. To date, all current antibiotics focus on inhibiting crucial enzymatic activities of their protein targets (i.e., trimethoprim for dihydrofolate reductase), thus disrupting in vitro essential gene functions. In contrast, we have previously reported the identification of virstatin, a small molecule that inhibits virulence regulation in Vibrio cholerae, thereby preventing intestinal colonization in an infant mouse model for cholera. Virstatin prevents expression of the two major V. cholerae virulence factors, cholera toxin (CT) and the toxin coregulated pilus, by inhibiting the virulence transcriptional activator ToxT. It has previously been described that the N-terminal domain of ToxT has the ability to form homodimers. We now demonstrate that virstatin inhibits ToxT dimerization, thus demonstrating that it further falls into a unique class of inhibitors that works by disrupting protein-protein interactions, particularly homodimerization. Using virstatin, truncation mutants of ToxT, and a virstatin-resistant mutant, we show that dimerization is required for ToxT activation of the ctx promoter. In contrast, ToxT dimerization does not appear to be required at all of the other ToxT-regulated promoters, suggesting multiple mechanisms may exist for its transcriptional activity.

authors

Shakhnovich EA,Hung DT,Pierson E,Lee K,Mekalanos JJ

doi

10.1073/pnas.0611643104

subject

Has Abstract

pub_date

2007-02-13 00:00:00

pages

2372-7

issue

7

eissn

0027-8424

issn

1091-6490

pii

0611643104

journal_volume

104

pub_type

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