A new class of inhibitors of the AraC family virulence regulator Vibrio cholerae ToxT.
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.
Department of Chemistry, Dartmouth College, Hanover, NH, 03755, USA.
Anne K
AK
Woodbrey
Department of Chemistry, Dartmouth College, Hanover, NH, 03755, USA.
Evans O
EO
Onyango
Department of Chemistry, Dartmouth College, Hanover, NH, 03755, USA.
Maria
M
Pellegrini
Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth, Hanover, NH, 03755, USA.
Gabriela
G
Kovacikova
Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth, Hanover, NH, 03755, USA.
Ronald K
RK
Taylor
Department of Chemistry, Dartmouth College, Hanover, NH, 03755, USA.
Gordon W
GW
Gribble
Department of Chemistry, Dartmouth College, Hanover, NH, 03755, USA.
F Jon
FJ
Kull
D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry*; D001665:Binding Sites; D003561:Cytarabine / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D015195:Drug Design; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D008968:Molecular Conformation; D011485:Protein Binding; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000737:chemistry*; D014734:Vibrio cholerae / Q000187:drug effects / Q000378:metabolism; D037521:Virulence Factors / Q000037:antagonists & inhibitors
D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D004268:DNA-Binding Proteins; D014157:Transcription Factors; D037521:Virulence Factors; D003561:Cytarabine; C075626:tcpN protein, Vibrio cholerae