Identification of small-molecule inhibitors of Yersinia pestis Type III secretion system YscN ATPase.

Yersinia pestis is a gram negative zoonotic pathogen responsible for causing bubonic and pneumonic plague in humans. The pathogen uses a type III secretion system (T3SS) to deliver virulence factors directly from bacterium into host mammalian cells. The system contains a single ATPase, YscN, necessa...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Wieslaw Swietnicki, Daniel Carmany, Michael Retford, Mark Guelta, Russell Dorsey, Joel Bozue, Michael S Lee, Mark A Olson
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2011
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/7c1ce5f18a864337a77e8ef9795e8d6b
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:7c1ce5f18a864337a77e8ef9795e8d6b
record_format	dspace
spelling	oai:doaj.org-article:7c1ce5f18a864337a77e8ef9795e8d6b2021-11-18T06:53:49ZIdentification of small-molecule inhibitors of Yersinia pestis Type III secretion system YscN ATPase.1932-620310.1371/journal.pone.0019716https://doaj.org/article/7c1ce5f18a864337a77e8ef9795e8d6b2011-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/21611119/?tool=EBIhttps://doaj.org/toc/1932-6203Yersinia pestis is a gram negative zoonotic pathogen responsible for causing bubonic and pneumonic plague in humans. The pathogen uses a type III secretion system (T3SS) to deliver virulence factors directly from bacterium into host mammalian cells. The system contains a single ATPase, YscN, necessary for delivery of virulence factors. In this work, we show that deletion of the catalytic domain of the yscN gene in Y. pestis CO92 attenuated the strain over three million-fold in the Swiss-Webster mouse model of bubonic plague. The result validates the YscN protein as a therapeutic target for plague. The catalytic domain of the YscN protein was made using recombinant methods and its ATPase activity was characterized in vitro. To identify candidate therapeutics, we tested computationally selected small molecules for inhibition of YscN ATPase activity. The best inhibitors had measured IC(50) values below 20 µM in an in vitro ATPase assay and were also found to inhibit the homologous BsaS protein from Burkholderia mallei animal-like T3SS at similar concentrations. Moreover, the compounds fully inhibited YopE secretion by attenuated Y. pestis in a bacterial cell culture and mammalian cells at µM concentrations. The data demonstrate the feasibility of targeting and inhibiting a critical protein transport ATPase of a bacterial virulence system. It is likely the same strategy could be applied to many other common human pathogens using type III secretion system, including enteropathogenic E. coli, Shigella flexneri, Salmonella typhimurium, and Burkholderia mallei/pseudomallei species.Wieslaw SwietnickiDaniel CarmanyMichael RetfordMark GueltaRussell DorseyJoel BozueMichael S LeeMark A OlsonPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 6, Iss 5, p e19716 (2011)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Wieslaw Swietnicki Daniel Carmany Michael Retford Mark Guelta Russell Dorsey Joel Bozue Michael S Lee Mark A Olson Identification of small-molecule inhibitors of Yersinia pestis Type III secretion system YscN ATPase.
description	Yersinia pestis is a gram negative zoonotic pathogen responsible for causing bubonic and pneumonic plague in humans. The pathogen uses a type III secretion system (T3SS) to deliver virulence factors directly from bacterium into host mammalian cells. The system contains a single ATPase, YscN, necessary for delivery of virulence factors. In this work, we show that deletion of the catalytic domain of the yscN gene in Y. pestis CO92 attenuated the strain over three million-fold in the Swiss-Webster mouse model of bubonic plague. The result validates the YscN protein as a therapeutic target for plague. The catalytic domain of the YscN protein was made using recombinant methods and its ATPase activity was characterized in vitro. To identify candidate therapeutics, we tested computationally selected small molecules for inhibition of YscN ATPase activity. The best inhibitors had measured IC(50) values below 20 µM in an in vitro ATPase assay and were also found to inhibit the homologous BsaS protein from Burkholderia mallei animal-like T3SS at similar concentrations. Moreover, the compounds fully inhibited YopE secretion by attenuated Y. pestis in a bacterial cell culture and mammalian cells at µM concentrations. The data demonstrate the feasibility of targeting and inhibiting a critical protein transport ATPase of a bacterial virulence system. It is likely the same strategy could be applied to many other common human pathogens using type III secretion system, including enteropathogenic E. coli, Shigella flexneri, Salmonella typhimurium, and Burkholderia mallei/pseudomallei species.
format	article
author	Wieslaw Swietnicki Daniel Carmany Michael Retford Mark Guelta Russell Dorsey Joel Bozue Michael S Lee Mark A Olson
author_facet	Wieslaw Swietnicki Daniel Carmany Michael Retford Mark Guelta Russell Dorsey Joel Bozue Michael S Lee Mark A Olson
author_sort	Wieslaw Swietnicki
title	Identification of small-molecule inhibitors of Yersinia pestis Type III secretion system YscN ATPase.
title_short	Identification of small-molecule inhibitors of Yersinia pestis Type III secretion system YscN ATPase.
title_full	Identification of small-molecule inhibitors of Yersinia pestis Type III secretion system YscN ATPase.
title_fullStr	Identification of small-molecule inhibitors of Yersinia pestis Type III secretion system YscN ATPase.
title_full_unstemmed	Identification of small-molecule inhibitors of Yersinia pestis Type III secretion system YscN ATPase.
title_sort	identification of small-molecule inhibitors of yersinia pestis type iii secretion system yscn atpase.
publisher	Public Library of Science (PLoS)
publishDate	2011
url	https://doaj.org/article/7c1ce5f18a864337a77e8ef9795e8d6b
work_keys_str_mv	AT wieslawswietnicki identificationofsmallmoleculeinhibitorsofyersiniapestistypeiiisecretionsystemyscnatpase AT danielcarmany identificationofsmallmoleculeinhibitorsofyersiniapestistypeiiisecretionsystemyscnatpase AT michaelretford identificationofsmallmoleculeinhibitorsofyersiniapestistypeiiisecretionsystemyscnatpase AT markguelta identificationofsmallmoleculeinhibitorsofyersiniapestistypeiiisecretionsystemyscnatpase AT russelldorsey identificationofsmallmoleculeinhibitorsofyersiniapestistypeiiisecretionsystemyscnatpase AT joelbozue identificationofsmallmoleculeinhibitorsofyersiniapestistypeiiisecretionsystemyscnatpase AT michaelslee identificationofsmallmoleculeinhibitorsofyersiniapestistypeiiisecretionsystemyscnatpase AT markaolson identificationofsmallmoleculeinhibitorsofyersiniapestistypeiiisecretionsystemyscnatpase
_version_	1718424237789675520

Identification of small-molecule inhibitors of Yersinia pestis Type III secretion system YscN ATPase.

Ejemplares similares