A new class of inhibitors of the AraC family virulence regulator

Woodbrey, Anne K.; Onyango, Evans O.; Pellegrini, Maria; Kovacikova, Gabriela; Taylor, Ronald K.; Gribble, Gordon W.; Kull, F. Jon

doi:10.1038/srep45011

A new class of inhibitors of the AraC family virulence regulator

Journal Article · Thu Mar 23 00:00:00 EDT 2017 · Scientific Reports

DOI:https://doi.org/10.1038/srep45011· OSTI ID:1624899

Woodbrey, Anne K. ^[1]; Onyango, Evans O. ^[2]; Pellegrini, Maria ^[2]; Kovacikova, Gabriela ^[3]; Taylor, Ronald K. ^[3]; Gribble, Gordon W. ^[2]; Kull, F. Jon ^[2]

Dartmouth College, Hanover, NH (United States). Dept. of Chemistry; DOE/OSTI
Dartmouth College, Hanover, NH (United States). Dept. of Chemistry
Geisel School of Medicine at Dartmouth, Hanover, NH (United States), Dept. of Microbiology and Immunology

Vibrio cholerae is responsible for the diarrheal disease cholera that infects millions of people worldwide. While vaccines protecting against cholera exist, and oral rehydration therapy is an effective treatment method, the disease will remain a global health threat until long-term solutions such as improved sanitation and access to clean water become widely available. Because of this, there is a pressing need for potent therapeutics that can either mitigate cholera symptoms, or act prophylactically to prevent the virulent effects of a cholera infection. Here we report the design, synthesis, and characterization of a set of compounds that bind and inhibit ToxT, the transcription factor that directly regulates the two primary V. cholerae virulence factors. Using the folded structure of the monounsaturated fatty acid observed in the X-ray structure of ToxT as a template, we designed ten novel compounds that inhibit the virulence cascade to a greater degree than any known inhibitor. Our findings provide a structural and functional basis for the development of viable antivirulence therapeutics that combat cholera and, potentially, other forms of bacterial pathogenic disease.

View Accepted Manuscript (DOE)

Research Organization:: Argonne National Lab. (ANL), Argonne, IL (United States)

Sponsoring Organization:: National Cancer Institute; National Institute of General Medical Sciences; National Institutes of Health; USDOE Office of Science (SC)

Grant/Contract Number:: AC02-06CH11357

OSTI ID:: 1624899

Journal Information:: Scientific Reports, Journal Name: Scientific Reports Journal Issue: 1 Vol. 7; ISSN 2045-2322

Publisher:: Nature Publishing GroupCopyright Statement

Country of Publication:: United States

Language:: English

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