Structure of the master regulator Rns reveals an inhibitor of enterotoxigenic Escherichia coli virulence regulons

Abstract Enteric infections caused by the gram-negative bacteria enterotoxigenic Escherichia coli (ETEC), Vibrio cholerae, Shigella flexneri, and Salmonella enterica are among the most common and affect billions of people each year. These bacteria control expression of virulence factors using a netw...

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Autores principales:	Charles R. Midgett, Kacey Marie Talbot, Jessica L. Day, George P. Munson, F. Jon Kull
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/534105fb0ec64ce69e4cffc37bd6633c
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spelling	oai:doaj.org-article:534105fb0ec64ce69e4cffc37bd6633c2021-12-02T16:35:46ZStructure of the master regulator Rns reveals an inhibitor of enterotoxigenic Escherichia coli virulence regulons10.1038/s41598-021-95123-22045-2322https://doaj.org/article/534105fb0ec64ce69e4cffc37bd6633c2021-08-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-95123-2https://doaj.org/toc/2045-2322Abstract Enteric infections caused by the gram-negative bacteria enterotoxigenic Escherichia coli (ETEC), Vibrio cholerae, Shigella flexneri, and Salmonella enterica are among the most common and affect billions of people each year. These bacteria control expression of virulence factors using a network of transcriptional regulators, some of which are modulated by small molecules as has been shown for ToxT, an AraC family member from V. cholerae. In ETEC the expression of many types of adhesive pili is dependent upon the AraC family member Rns. We present here the 3 Å crystal structure of Rns and show it closely resembles ToxT. Rns crystallized as a dimer via an interface similar to that observed in other dimeric AraC’s. Furthermore, the structure of Rns revealed the presence of a ligand, decanoic acid, that inhibits its activity in a manner similar to the fatty acid mediated inhibition observed for ToxT and the S. enterica homologue HilD. Together, these results support our hypothesis that fatty acids regulate virulence controlling AraC family members in a common manner across a number of enteric pathogens. Furthermore, for the first time this work identifies a small molecule capable of inhibiting the ETEC Rns regulon, providing a basis for development of therapeutics against this deadly human pathogen.Charles R. MidgettKacey Marie TalbotJessica L. DayGeorge P. MunsonF. Jon KullNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-13 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Charles R. Midgett Kacey Marie Talbot Jessica L. Day George P. Munson F. Jon Kull Structure of the master regulator Rns reveals an inhibitor of enterotoxigenic Escherichia coli virulence regulons
description	Abstract Enteric infections caused by the gram-negative bacteria enterotoxigenic Escherichia coli (ETEC), Vibrio cholerae, Shigella flexneri, and Salmonella enterica are among the most common and affect billions of people each year. These bacteria control expression of virulence factors using a network of transcriptional regulators, some of which are modulated by small molecules as has been shown for ToxT, an AraC family member from V. cholerae. In ETEC the expression of many types of adhesive pili is dependent upon the AraC family member Rns. We present here the 3 Å crystal structure of Rns and show it closely resembles ToxT. Rns crystallized as a dimer via an interface similar to that observed in other dimeric AraC’s. Furthermore, the structure of Rns revealed the presence of a ligand, decanoic acid, that inhibits its activity in a manner similar to the fatty acid mediated inhibition observed for ToxT and the S. enterica homologue HilD. Together, these results support our hypothesis that fatty acids regulate virulence controlling AraC family members in a common manner across a number of enteric pathogens. Furthermore, for the first time this work identifies a small molecule capable of inhibiting the ETEC Rns regulon, providing a basis for development of therapeutics against this deadly human pathogen.
format	article
author	Charles R. Midgett Kacey Marie Talbot Jessica L. Day George P. Munson F. Jon Kull
author_facet	Charles R. Midgett Kacey Marie Talbot Jessica L. Day George P. Munson F. Jon Kull
author_sort	Charles R. Midgett
title	Structure of the master regulator Rns reveals an inhibitor of enterotoxigenic Escherichia coli virulence regulons
title_short	Structure of the master regulator Rns reveals an inhibitor of enterotoxigenic Escherichia coli virulence regulons
title_full	Structure of the master regulator Rns reveals an inhibitor of enterotoxigenic Escherichia coli virulence regulons
title_fullStr	Structure of the master regulator Rns reveals an inhibitor of enterotoxigenic Escherichia coli virulence regulons
title_full_unstemmed	Structure of the master regulator Rns reveals an inhibitor of enterotoxigenic Escherichia coli virulence regulons
title_sort	structure of the master regulator rns reveals an inhibitor of enterotoxigenic escherichia coli virulence regulons
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/534105fb0ec64ce69e4cffc37bd6633c
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Structure of the master regulator Rns reveals an inhibitor of enterotoxigenic Escherichia coli virulence regulons

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