Phosphopantetheinyl transferase binding and inhibition by amidino-urea and hydroxypyrimidinethione compounds

Abstract Owing to their role in activating enzymes essential for bacterial viability and pathogenicity, phosphopantetheinyl transferases represent novel and attractive drug targets. In this work, we examined the inhibitory effect of the aminido-urea 8918 compound against the phosphopantetheinyl tran...

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Autores principales:	Coralie Carivenc, Laurent Maveyraud, Claire Blanger, Stéphanie Ballereau, Coralie Roy-Camille, Minh Chau Nguyen, Yves Génisson, Christophe Guilhot, Christian Chalut, Jean-Denis Pedelacq, Lionel Mourey
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/f57ec08b40274ca4ab42e00bdf4c4481
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spelling	oai:doaj.org-article:f57ec08b40274ca4ab42e00bdf4c44812021-12-02T19:12:33ZPhosphopantetheinyl transferase binding and inhibition by amidino-urea and hydroxypyrimidinethione compounds10.1038/s41598-021-97197-42045-2322https://doaj.org/article/f57ec08b40274ca4ab42e00bdf4c44812021-09-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-97197-4https://doaj.org/toc/2045-2322Abstract Owing to their role in activating enzymes essential for bacterial viability and pathogenicity, phosphopantetheinyl transferases represent novel and attractive drug targets. In this work, we examined the inhibitory effect of the aminido-urea 8918 compound against the phosphopantetheinyl transferases PptAb from Mycobacterium abscessus and PcpS from Pseudomonas aeruginosa, two pathogenic bacteria associated with cystic fibrosis and bronchiectasis, respectively. Compound 8918 exhibits inhibitory activity against PptAb but displays no activity against PcpS in vitro, while no antimicrobial activity against Mycobacterium abscessus or Pseudomonas aeruginosa could be detected. X-ray crystallographic analysis of 8918 bound to PptAb-CoA alone and in complex with an acyl carrier protein domain in addition to the crystal structure of PcpS in complex with CoA revealed the structural basis for the inhibition mechanism of PptAb by 8918 and its ineffectiveness against PcpS. Finally, in crystallo screening of potent inhibitors from the National Cancer Institute library identified a hydroxypyrimidinethione derivative that binds PptAb. Both compounds could serve as scaffolds for the future development of phosphopantetheinyl transferases inhibitors.Coralie CarivencLaurent MaveyraudClaire BlangerStéphanie BallereauCoralie Roy-CamilleMinh Chau NguyenYves GénissonChristophe GuilhotChristian ChalutJean-Denis PedelacqLionel MoureyNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-10 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Coralie Carivenc Laurent Maveyraud Claire Blanger Stéphanie Ballereau Coralie Roy-Camille Minh Chau Nguyen Yves Génisson Christophe Guilhot Christian Chalut Jean-Denis Pedelacq Lionel Mourey Phosphopantetheinyl transferase binding and inhibition by amidino-urea and hydroxypyrimidinethione compounds
description	Abstract Owing to their role in activating enzymes essential for bacterial viability and pathogenicity, phosphopantetheinyl transferases represent novel and attractive drug targets. In this work, we examined the inhibitory effect of the aminido-urea 8918 compound against the phosphopantetheinyl transferases PptAb from Mycobacterium abscessus and PcpS from Pseudomonas aeruginosa, two pathogenic bacteria associated with cystic fibrosis and bronchiectasis, respectively. Compound 8918 exhibits inhibitory activity against PptAb but displays no activity against PcpS in vitro, while no antimicrobial activity against Mycobacterium abscessus or Pseudomonas aeruginosa could be detected. X-ray crystallographic analysis of 8918 bound to PptAb-CoA alone and in complex with an acyl carrier protein domain in addition to the crystal structure of PcpS in complex with CoA revealed the structural basis for the inhibition mechanism of PptAb by 8918 and its ineffectiveness against PcpS. Finally, in crystallo screening of potent inhibitors from the National Cancer Institute library identified a hydroxypyrimidinethione derivative that binds PptAb. Both compounds could serve as scaffolds for the future development of phosphopantetheinyl transferases inhibitors.
format	article
author	Coralie Carivenc Laurent Maveyraud Claire Blanger Stéphanie Ballereau Coralie Roy-Camille Minh Chau Nguyen Yves Génisson Christophe Guilhot Christian Chalut Jean-Denis Pedelacq Lionel Mourey
author_facet	Coralie Carivenc Laurent Maveyraud Claire Blanger Stéphanie Ballereau Coralie Roy-Camille Minh Chau Nguyen Yves Génisson Christophe Guilhot Christian Chalut Jean-Denis Pedelacq Lionel Mourey
author_sort	Coralie Carivenc
title	Phosphopantetheinyl transferase binding and inhibition by amidino-urea and hydroxypyrimidinethione compounds
title_short	Phosphopantetheinyl transferase binding and inhibition by amidino-urea and hydroxypyrimidinethione compounds
title_full	Phosphopantetheinyl transferase binding and inhibition by amidino-urea and hydroxypyrimidinethione compounds
title_fullStr	Phosphopantetheinyl transferase binding and inhibition by amidino-urea and hydroxypyrimidinethione compounds
title_full_unstemmed	Phosphopantetheinyl transferase binding and inhibition by amidino-urea and hydroxypyrimidinethione compounds
title_sort	phosphopantetheinyl transferase binding and inhibition by amidino-urea and hydroxypyrimidinethione compounds
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/f57ec08b40274ca4ab42e00bdf4c4481
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Phosphopantetheinyl transferase binding and inhibition by amidino-urea and hydroxypyrimidinethione compounds

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