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Interrogation of the Pathogen Box reveals small molecule ligands against the mycobacterial trehalose transporter LpqY-SugABC

Tuberculosis, caused by Mycobacterium tuberculosis, claims ∼1.5 million lives annually. Effective chemotherapy is essential to control TB, however the emergence of drug-resistant strains of TB have seriously threatened global attempts to control and eradicate this deadly pathogen. Trehalose recyclin...

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Autores principales: Radhakrishnan, Anjana, Brown, Chelsea M., Guy, Collette S., Cooper, Charlotte, Pacheco-Gomez, Raul, Stansfeld, Phillip J., Fullam, Elizabeth
Formato: Online Artículo Texto
Lenguaje:English
Publicado: RSC 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9579956/
https://www.ncbi.nlm.nih.gov/pubmed/36320433
http://dx.doi.org/10.1039/d2md00104g
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author Radhakrishnan, Anjana
Brown, Chelsea M.
Guy, Collette S.
Cooper, Charlotte
Pacheco-Gomez, Raul
Stansfeld, Phillip J.
Fullam, Elizabeth
author_facet Radhakrishnan, Anjana
Brown, Chelsea M.
Guy, Collette S.
Cooper, Charlotte
Pacheco-Gomez, Raul
Stansfeld, Phillip J.
Fullam, Elizabeth
author_sort Radhakrishnan, Anjana
collection PubMed
description Tuberculosis, caused by Mycobacterium tuberculosis, claims ∼1.5 million lives annually. Effective chemotherapy is essential to control TB, however the emergence of drug-resistant strains of TB have seriously threatened global attempts to control and eradicate this deadly pathogen. Trehalose recycling via the LpqY-SugABC importer is essential for the virulence and survival of Mtb and inhibiting or hijacking this transport system is an attractive approach for the development of novel anti-tubercular and diagnostic agents. Therefore, we interrogated the drug-like compounds in the open-source Medicines for Malaria Pathogen Box and successfully identified seven compounds from the TB, kinetoplastids and reference compound disease sets that recognise LpqY. The molecules have diverse chemical scaffolds, are not specific trehalose analogues, and may be used as novel templates to facilitate the development of therapeutics that kill Mtb with a novel mechanism of action via the mycobacterial trehalose LpqY-SugABC transport system.
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spelling pubmed-95799562022-10-31 Interrogation of the Pathogen Box reveals small molecule ligands against the mycobacterial trehalose transporter LpqY-SugABC Radhakrishnan, Anjana Brown, Chelsea M. Guy, Collette S. Cooper, Charlotte Pacheco-Gomez, Raul Stansfeld, Phillip J. Fullam, Elizabeth RSC Med Chem Chemistry Tuberculosis, caused by Mycobacterium tuberculosis, claims ∼1.5 million lives annually. Effective chemotherapy is essential to control TB, however the emergence of drug-resistant strains of TB have seriously threatened global attempts to control and eradicate this deadly pathogen. Trehalose recycling via the LpqY-SugABC importer is essential for the virulence and survival of Mtb and inhibiting or hijacking this transport system is an attractive approach for the development of novel anti-tubercular and diagnostic agents. Therefore, we interrogated the drug-like compounds in the open-source Medicines for Malaria Pathogen Box and successfully identified seven compounds from the TB, kinetoplastids and reference compound disease sets that recognise LpqY. The molecules have diverse chemical scaffolds, are not specific trehalose analogues, and may be used as novel templates to facilitate the development of therapeutics that kill Mtb with a novel mechanism of action via the mycobacterial trehalose LpqY-SugABC transport system. RSC 2022-08-16 /pmc/articles/PMC9579956/ /pubmed/36320433 http://dx.doi.org/10.1039/d2md00104g Text en This journal is © The Royal Society of Chemistry https://creativecommons.org/licenses/by/3.0/
spellingShingle Chemistry
Radhakrishnan, Anjana
Brown, Chelsea M.
Guy, Collette S.
Cooper, Charlotte
Pacheco-Gomez, Raul
Stansfeld, Phillip J.
Fullam, Elizabeth
Interrogation of the Pathogen Box reveals small molecule ligands against the mycobacterial trehalose transporter LpqY-SugABC
title Interrogation of the Pathogen Box reveals small molecule ligands against the mycobacterial trehalose transporter LpqY-SugABC
title_full Interrogation of the Pathogen Box reveals small molecule ligands against the mycobacterial trehalose transporter LpqY-SugABC
title_fullStr Interrogation of the Pathogen Box reveals small molecule ligands against the mycobacterial trehalose transporter LpqY-SugABC
title_full_unstemmed Interrogation of the Pathogen Box reveals small molecule ligands against the mycobacterial trehalose transporter LpqY-SugABC
title_short Interrogation of the Pathogen Box reveals small molecule ligands against the mycobacterial trehalose transporter LpqY-SugABC
title_sort interrogation of the pathogen box reveals small molecule ligands against the mycobacterial trehalose transporter lpqy-sugabc
topic Chemistry
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9579956/
https://www.ncbi.nlm.nih.gov/pubmed/36320433
http://dx.doi.org/10.1039/d2md00104g
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