Small-Molecule Inhibitors of <italic toggle="yes">toxT</italic> Expression in <named-content content-type="genus-species">Vibrio cholerae</named-content>

ABSTRACT Vibrio cholerae, a Gram-negative bacterium, infects humans and causes cholera, a severe disease characterized by vomiting and diarrhea. These symptoms are primarily caused by cholera toxin (CT), whose production by V. cholerae is tightly regulated by the virulence cascade. In this study, we...

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Autores principales:	Rebecca Anthouard, Victor J. DiRita
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2013
Materias:	Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/33209e87b72641268b1bf853f9343448
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spelling	oai:doaj.org-article:33209e87b72641268b1bf853f93434482021-11-15T15:43:09ZSmall-Molecule Inhibitors of <italic toggle="yes">toxT</italic> Expression in <named-content content-type="genus-species">Vibrio cholerae</named-content>10.1128/mBio.00403-132150-7511https://doaj.org/article/33209e87b72641268b1bf853f93434482013-08-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.00403-13https://doaj.org/toc/2150-7511ABSTRACT Vibrio cholerae, a Gram-negative bacterium, infects humans and causes cholera, a severe disease characterized by vomiting and diarrhea. These symptoms are primarily caused by cholera toxin (CT), whose production by V. cholerae is tightly regulated by the virulence cascade. In this study, we designed and carried out a high-throughput chemical genetic screen to identify inhibitors of the virulence cascade. We identified three compounds, which we named toxtazin A and toxtazin B and Bʹ, representing two novel classes of toxT transcription inhibitors. All three compounds reduce production of both CT and the toxin-coregulated pilus (TCP), an important colonization factor. We present evidence that toxtazin A works at the level of the toxT promoter and that toxtazins B and Bʹ work at the level of the tcpP promoter. Treatment with toxtazin B results in a 100-fold reduction in colonization in an infant mouse model of infection, though toxtazin A did not reduce colonization at the concentrations tested. These results add to the growing body of literature indicating that small-molecule inhibitors of virulence genes could be developed to treat infections, as alternatives to antibiotics become increasingly needed. IMPORTANCE V. cholerae caused more than 580,000 infections worldwide in 2011 alone (WHO, Wkly. Epidemiol. Rec. 87:289-304, 2012). Cholera is treated with an oral rehydration therapy consisting of water, glucose, and electrolytes. However, as V. cholerae is transmitted via contaminated water, treatment can be difficult for communities whose water source is contaminated. In this study, we address the need for new therapeutic approaches by targeting the production of the main virulence factor, cholera toxin (CT). The high-throughput screen presented here led to the identification of two novel classes of inhibitors of the virulence cascade in V. cholerae, toxtazin A and toxtazins B and Bʹ. We demonstrate that (i) small-molecule inhibitors of virulence gene production can be identified in a high-throughput screen, (ii) targeting virulence gene production is an effective therapeutic strategy, and (iii) small-molecule inhibitors can uncover unknown layers of gene regulation, even in well-studied regulatory cascades.Rebecca AnthouardVictor J. DiRitaAmerican Society for MicrobiologyarticleMicrobiologyQR1-502ENmBio, Vol 4, Iss 4 (2013)
institution	DOAJ
collection	DOAJ
language	EN
topic	Microbiology QR1-502
spellingShingle	Microbiology QR1-502 Rebecca Anthouard Victor J. DiRita Small-Molecule Inhibitors of <italic toggle="yes">toxT</italic> Expression in <named-content content-type="genus-species">Vibrio cholerae</named-content>
description	ABSTRACT Vibrio cholerae, a Gram-negative bacterium, infects humans and causes cholera, a severe disease characterized by vomiting and diarrhea. These symptoms are primarily caused by cholera toxin (CT), whose production by V. cholerae is tightly regulated by the virulence cascade. In this study, we designed and carried out a high-throughput chemical genetic screen to identify inhibitors of the virulence cascade. We identified three compounds, which we named toxtazin A and toxtazin B and Bʹ, representing two novel classes of toxT transcription inhibitors. All three compounds reduce production of both CT and the toxin-coregulated pilus (TCP), an important colonization factor. We present evidence that toxtazin A works at the level of the toxT promoter and that toxtazins B and Bʹ work at the level of the tcpP promoter. Treatment with toxtazin B results in a 100-fold reduction in colonization in an infant mouse model of infection, though toxtazin A did not reduce colonization at the concentrations tested. These results add to the growing body of literature indicating that small-molecule inhibitors of virulence genes could be developed to treat infections, as alternatives to antibiotics become increasingly needed. IMPORTANCE V. cholerae caused more than 580,000 infections worldwide in 2011 alone (WHO, Wkly. Epidemiol. Rec. 87:289-304, 2012). Cholera is treated with an oral rehydration therapy consisting of water, glucose, and electrolytes. However, as V. cholerae is transmitted via contaminated water, treatment can be difficult for communities whose water source is contaminated. In this study, we address the need for new therapeutic approaches by targeting the production of the main virulence factor, cholera toxin (CT). The high-throughput screen presented here led to the identification of two novel classes of inhibitors of the virulence cascade in V. cholerae, toxtazin A and toxtazins B and Bʹ. We demonstrate that (i) small-molecule inhibitors of virulence gene production can be identified in a high-throughput screen, (ii) targeting virulence gene production is an effective therapeutic strategy, and (iii) small-molecule inhibitors can uncover unknown layers of gene regulation, even in well-studied regulatory cascades.
format	article
author	Rebecca Anthouard Victor J. DiRita
author_facet	Rebecca Anthouard Victor J. DiRita
author_sort	Rebecca Anthouard
title	Small-Molecule Inhibitors of <italic toggle="yes">toxT</italic> Expression in <named-content content-type="genus-species">Vibrio cholerae</named-content>
title_short	Small-Molecule Inhibitors of <italic toggle="yes">toxT</italic> Expression in <named-content content-type="genus-species">Vibrio cholerae</named-content>
title_full	Small-Molecule Inhibitors of <italic toggle="yes">toxT</italic> Expression in <named-content content-type="genus-species">Vibrio cholerae</named-content>
title_fullStr	Small-Molecule Inhibitors of <italic toggle="yes">toxT</italic> Expression in <named-content content-type="genus-species">Vibrio cholerae</named-content>
title_full_unstemmed	Small-Molecule Inhibitors of <italic toggle="yes">toxT</italic> Expression in <named-content content-type="genus-species">Vibrio cholerae</named-content>
title_sort	small-molecule inhibitors of <italic toggle="yes">toxt</italic> expression in <named-content content-type="genus-species">vibrio cholerae</named-content>
publisher	American Society for Microbiology
publishDate	2013
url	https://doaj.org/article/33209e87b72641268b1bf853f9343448
work_keys_str_mv	AT rebeccaanthouard smallmoleculeinhibitorsofitalictoggleyestoxtitalicexpressioninnamedcontentcontenttypegenusspeciesvibriocholeraenamedcontent AT victorjdirita smallmoleculeinhibitorsofitalictoggleyestoxtitalicexpressioninnamedcontentcontenttypegenusspeciesvibriocholeraenamedcontent
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Small-Molecule Inhibitors of <italic toggle="yes">toxT</italic> Expression in <named-content content-type="genus-species">Vibrio cholerae</named-content>

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