Structure-Based Design of MptpB Inhibitors That Reduce Multidrug-Resistant Mycobacterium tuberculosis Survival and Infection Burden in Vivo

[Image: see text] Mycobacterium tuberculosis protein-tyrosine-phosphatase B (MptpB) is a secreted virulence factor that subverts antimicrobial activity in the host. We report here the structure-based design of selective MptpB inhibitors that reduce survival of multidrug-resistant tuberculosis strain...

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Autores principales: Vickers, Clare F., Silva, Ana P. G., Chakraborty, Ajanta, Fernandez, Paulina, Kurepina, Natalia, Saville, Charis, Naranjo, Yandi, Pons, Miquel, Schnettger, Laura S., Gutierrez, Maximiliano G., Park, Steven, Kreiswith, Barry N., Perlin, David S., Thomas, Eric J., Cavet, Jennifer S., Tabernero, Lydia
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Chemical Society 2018
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6459586/
https://www.ncbi.nlm.nih.gov/pubmed/30153005
http://dx.doi.org/10.1021/acs.jmedchem.8b00832
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author Vickers, Clare F.
Silva, Ana P. G.
Chakraborty, Ajanta
Fernandez, Paulina
Kurepina, Natalia
Saville, Charis
Naranjo, Yandi
Pons, Miquel
Schnettger, Laura S.
Gutierrez, Maximiliano G.
Park, Steven
Kreiswith, Barry N.
Perlin, David S.
Thomas, Eric J.
Cavet, Jennifer S.
Tabernero, Lydia
author_facet Vickers, Clare F.
Silva, Ana P. G.
Chakraborty, Ajanta
Fernandez, Paulina
Kurepina, Natalia
Saville, Charis
Naranjo, Yandi
Pons, Miquel
Schnettger, Laura S.
Gutierrez, Maximiliano G.
Park, Steven
Kreiswith, Barry N.
Perlin, David S.
Thomas, Eric J.
Cavet, Jennifer S.
Tabernero, Lydia
author_sort Vickers, Clare F.
collection PubMed
description [Image: see text] Mycobacterium tuberculosis protein-tyrosine-phosphatase B (MptpB) is a secreted virulence factor that subverts antimicrobial activity in the host. We report here the structure-based design of selective MptpB inhibitors that reduce survival of multidrug-resistant tuberculosis strains in macrophages and enhance killing efficacy by first-line antibiotics. Monotherapy with an orally bioavailable MptpB inhibitor reduces infection burden in acute and chronic guinea pig models and improves the overall pathology. Our findings provide a new paradigm for tuberculosis treatment.
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spelling pubmed-64595862019-04-12 Structure-Based Design of MptpB Inhibitors That Reduce Multidrug-Resistant Mycobacterium tuberculosis Survival and Infection Burden in Vivo Vickers, Clare F. Silva, Ana P. G. Chakraborty, Ajanta Fernandez, Paulina Kurepina, Natalia Saville, Charis Naranjo, Yandi Pons, Miquel Schnettger, Laura S. Gutierrez, Maximiliano G. Park, Steven Kreiswith, Barry N. Perlin, David S. Thomas, Eric J. Cavet, Jennifer S. Tabernero, Lydia J Med Chem [Image: see text] Mycobacterium tuberculosis protein-tyrosine-phosphatase B (MptpB) is a secreted virulence factor that subverts antimicrobial activity in the host. We report here the structure-based design of selective MptpB inhibitors that reduce survival of multidrug-resistant tuberculosis strains in macrophages and enhance killing efficacy by first-line antibiotics. Monotherapy with an orally bioavailable MptpB inhibitor reduces infection burden in acute and chronic guinea pig models and improves the overall pathology. Our findings provide a new paradigm for tuberculosis treatment. American Chemical Society 2018-08-28 2018-09-27 /pmc/articles/PMC6459586/ /pubmed/30153005 http://dx.doi.org/10.1021/acs.jmedchem.8b00832 Text en Copyright © 2018 American Chemical Society This is an open access article published under a Creative Commons Attribution (CC-BY) License (http://pubs.acs.org/page/policy/authorchoice_ccby_termsofuse.html) , which permits unrestricted use, distribution and reproduction in any medium, provided the author and source are cited.
spellingShingle Vickers, Clare F.
Silva, Ana P. G.
Chakraborty, Ajanta
Fernandez, Paulina
Kurepina, Natalia
Saville, Charis
Naranjo, Yandi
Pons, Miquel
Schnettger, Laura S.
Gutierrez, Maximiliano G.
Park, Steven
Kreiswith, Barry N.
Perlin, David S.
Thomas, Eric J.
Cavet, Jennifer S.
Tabernero, Lydia
Structure-Based Design of MptpB Inhibitors That Reduce Multidrug-Resistant Mycobacterium tuberculosis Survival and Infection Burden in Vivo
title Structure-Based Design of MptpB Inhibitors That Reduce Multidrug-Resistant Mycobacterium tuberculosis Survival and Infection Burden in Vivo
title_full Structure-Based Design of MptpB Inhibitors That Reduce Multidrug-Resistant Mycobacterium tuberculosis Survival and Infection Burden in Vivo
title_fullStr Structure-Based Design of MptpB Inhibitors That Reduce Multidrug-Resistant Mycobacterium tuberculosis Survival and Infection Burden in Vivo
title_full_unstemmed Structure-Based Design of MptpB Inhibitors That Reduce Multidrug-Resistant Mycobacterium tuberculosis Survival and Infection Burden in Vivo
title_short Structure-Based Design of MptpB Inhibitors That Reduce Multidrug-Resistant Mycobacterium tuberculosis Survival and Infection Burden in Vivo
title_sort structure-based design of mptpb inhibitors that reduce multidrug-resistant mycobacterium tuberculosis survival and infection burden in vivo
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6459586/
https://www.ncbi.nlm.nih.gov/pubmed/30153005
http://dx.doi.org/10.1021/acs.jmedchem.8b00832
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