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Whole Cell Active Inhibitors of Mycobacterial Lipoamide Dehydrogenase Afford Selectivity over the Human Enzyme through Tight Binding Interactions

[Image: see text] Tuberculosis remains a leading cause of death from a single bacterial infection worldwide. Efforts to develop new treatment options call for expansion into an unexplored target space to expand the drug pipeline and bypass resistance to current antibiotics. Lipoamide dehydrogenase i...

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Autores principales: Ginn, John, Jiang, Xiuju, Sun, Shan, Michino, Mayako, Huggins, David J., Mbambo, Zodwa, Jansen, Robert, Rhee, Kyu Y., Arango, Nancy, Lima, Christopher D., Liverton, Nigel, Imaeda, Toshihiro, Okamoto, Rei, Kuroita, Takanobu, Aso, Kazuyoshi, Stamford, Andrew, Foley, Michael, Meinke, Peter T., Nathan, Carl, Bryk, Ruslana
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Chemical Society 2021
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7888283/
https://www.ncbi.nlm.nih.gov/pubmed/33527832
http://dx.doi.org/10.1021/acsinfecdis.0c00788
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author Ginn, John
Jiang, Xiuju
Sun, Shan
Michino, Mayako
Huggins, David J.
Mbambo, Zodwa
Jansen, Robert
Rhee, Kyu Y.
Arango, Nancy
Lima, Christopher D.
Liverton, Nigel
Imaeda, Toshihiro
Okamoto, Rei
Kuroita, Takanobu
Aso, Kazuyoshi
Stamford, Andrew
Foley, Michael
Meinke, Peter T.
Nathan, Carl
Bryk, Ruslana
author_facet Ginn, John
Jiang, Xiuju
Sun, Shan
Michino, Mayako
Huggins, David J.
Mbambo, Zodwa
Jansen, Robert
Rhee, Kyu Y.
Arango, Nancy
Lima, Christopher D.
Liverton, Nigel
Imaeda, Toshihiro
Okamoto, Rei
Kuroita, Takanobu
Aso, Kazuyoshi
Stamford, Andrew
Foley, Michael
Meinke, Peter T.
Nathan, Carl
Bryk, Ruslana
author_sort Ginn, John
collection PubMed
description [Image: see text] Tuberculosis remains a leading cause of death from a single bacterial infection worldwide. Efforts to develop new treatment options call for expansion into an unexplored target space to expand the drug pipeline and bypass resistance to current antibiotics. Lipoamide dehydrogenase is a metabolic and antioxidant enzyme critical for mycobacterial growth and survival in mice. Sulfonamide analogs were previously identified as potent and selective inhibitors of mycobacterial lipoamide dehydrogenase in vitro but lacked activity against whole mycobacteria. Here we present the development of analogs with improved permeability, potency, and selectivity, which inhibit the growth of Mycobacterium tuberculosis in axenic culture on carbohydrates and within mouse primary macrophages. They increase intrabacterial pyruvate levels, supporting their on-target activity within mycobacteria. Distinct modalities of binding between the mycobacterial and human enzymes contribute to improved potency and hence selectivity through induced-fit tight binding interactions within the mycobacterial but not human enzyme, as indicated by kinetic analysis and crystallography.
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spelling pubmed-78882832021-02-18 Whole Cell Active Inhibitors of Mycobacterial Lipoamide Dehydrogenase Afford Selectivity over the Human Enzyme through Tight Binding Interactions Ginn, John Jiang, Xiuju Sun, Shan Michino, Mayako Huggins, David J. Mbambo, Zodwa Jansen, Robert Rhee, Kyu Y. Arango, Nancy Lima, Christopher D. Liverton, Nigel Imaeda, Toshihiro Okamoto, Rei Kuroita, Takanobu Aso, Kazuyoshi Stamford, Andrew Foley, Michael Meinke, Peter T. Nathan, Carl Bryk, Ruslana ACS Infect Dis [Image: see text] Tuberculosis remains a leading cause of death from a single bacterial infection worldwide. Efforts to develop new treatment options call for expansion into an unexplored target space to expand the drug pipeline and bypass resistance to current antibiotics. Lipoamide dehydrogenase is a metabolic and antioxidant enzyme critical for mycobacterial growth and survival in mice. Sulfonamide analogs were previously identified as potent and selective inhibitors of mycobacterial lipoamide dehydrogenase in vitro but lacked activity against whole mycobacteria. Here we present the development of analogs with improved permeability, potency, and selectivity, which inhibit the growth of Mycobacterium tuberculosis in axenic culture on carbohydrates and within mouse primary macrophages. They increase intrabacterial pyruvate levels, supporting their on-target activity within mycobacteria. Distinct modalities of binding between the mycobacterial and human enzymes contribute to improved potency and hence selectivity through induced-fit tight binding interactions within the mycobacterial but not human enzyme, as indicated by kinetic analysis and crystallography. American Chemical Society 2021-02-02 2021-02-12 /pmc/articles/PMC7888283/ /pubmed/33527832 http://dx.doi.org/10.1021/acsinfecdis.0c00788 Text en © 2021 American Chemical Society Made available through a Creative Commons CC-BY-NC-ND License (http://pubs.acs.org/page/policy/authorchoice_ccbyncnd_termsofuse.html)
spellingShingle Ginn, John
Jiang, Xiuju
Sun, Shan
Michino, Mayako
Huggins, David J.
Mbambo, Zodwa
Jansen, Robert
Rhee, Kyu Y.
Arango, Nancy
Lima, Christopher D.
Liverton, Nigel
Imaeda, Toshihiro
Okamoto, Rei
Kuroita, Takanobu
Aso, Kazuyoshi
Stamford, Andrew
Foley, Michael
Meinke, Peter T.
Nathan, Carl
Bryk, Ruslana
Whole Cell Active Inhibitors of Mycobacterial Lipoamide Dehydrogenase Afford Selectivity over the Human Enzyme through Tight Binding Interactions
title Whole Cell Active Inhibitors of Mycobacterial Lipoamide Dehydrogenase Afford Selectivity over the Human Enzyme through Tight Binding Interactions
title_full Whole Cell Active Inhibitors of Mycobacterial Lipoamide Dehydrogenase Afford Selectivity over the Human Enzyme through Tight Binding Interactions
title_fullStr Whole Cell Active Inhibitors of Mycobacterial Lipoamide Dehydrogenase Afford Selectivity over the Human Enzyme through Tight Binding Interactions
title_full_unstemmed Whole Cell Active Inhibitors of Mycobacterial Lipoamide Dehydrogenase Afford Selectivity over the Human Enzyme through Tight Binding Interactions
title_short Whole Cell Active Inhibitors of Mycobacterial Lipoamide Dehydrogenase Afford Selectivity over the Human Enzyme through Tight Binding Interactions
title_sort whole cell active inhibitors of mycobacterial lipoamide dehydrogenase afford selectivity over the human enzyme through tight binding interactions
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7888283/
https://www.ncbi.nlm.nih.gov/pubmed/33527832
http://dx.doi.org/10.1021/acsinfecdis.0c00788
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