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Whole-Cell Screen of Fragment Library Identifies Gut Microbiota Metabolite Indole Propionic Acid as Antitubercular
Several key antituberculosis drugs, including pyrazinamide, with a molecular mass of 123.1 g/mol, are smaller than the usual drug-like molecules. Current drug discovery efforts focus on the screening of larger compounds with molecular masses centered around 400 to 500 g/mol. Fragment (molecular mass...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Society for Microbiology
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5826148/ https://www.ncbi.nlm.nih.gov/pubmed/29229639 http://dx.doi.org/10.1128/AAC.01571-17 |
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author | Negatu, Dereje A. Liu, Joe J. J. Zimmerman, Matthew Kaya, Firat Dartois, Véronique Aldrich, Courtney C. Gengenbacher, Martin Dick, Thomas |
author_facet | Negatu, Dereje A. Liu, Joe J. J. Zimmerman, Matthew Kaya, Firat Dartois, Véronique Aldrich, Courtney C. Gengenbacher, Martin Dick, Thomas |
author_sort | Negatu, Dereje A. |
collection | PubMed |
description | Several key antituberculosis drugs, including pyrazinamide, with a molecular mass of 123.1 g/mol, are smaller than the usual drug-like molecules. Current drug discovery efforts focus on the screening of larger compounds with molecular masses centered around 400 to 500 g/mol. Fragment (molecular mass < 300 g/mol) libraries have not been systematically explored for antitubercular activity. Here we screened a collection of 1,000 fragments, present in the Maybridge Ro3 library, for whole-cell activity against Mycobacterium tuberculosis. Twenty-nine primary hits showed dose-dependent growth inhibition equal to or better than that of pyrazinamide. The most potent hit, indole propionic acid [IPA; 3-(1H-indol-3-yl)propanoic acid], a metabolite produced by the gut microbiota, was profiled in vivo. The molecule was well tolerated in mice and showed adequate pharmacokinetic properties. In a mouse model of acute M. tuberculosis infection, IPA reduced the bacterial load in the spleen 7-fold. Our results suggest that IPA should be evaluated as an add-on to current regimens and that fragment libraries should be further explored to identify antimycobacterial lead candidates. |
format | Online Article Text |
id | pubmed-5826148 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | American Society for Microbiology |
record_format | MEDLINE/PubMed |
spelling | pubmed-58261482018-08-23 Whole-Cell Screen of Fragment Library Identifies Gut Microbiota Metabolite Indole Propionic Acid as Antitubercular Negatu, Dereje A. Liu, Joe J. J. Zimmerman, Matthew Kaya, Firat Dartois, Véronique Aldrich, Courtney C. Gengenbacher, Martin Dick, Thomas Antimicrob Agents Chemother Experimental Therapeutics Several key antituberculosis drugs, including pyrazinamide, with a molecular mass of 123.1 g/mol, are smaller than the usual drug-like molecules. Current drug discovery efforts focus on the screening of larger compounds with molecular masses centered around 400 to 500 g/mol. Fragment (molecular mass < 300 g/mol) libraries have not been systematically explored for antitubercular activity. Here we screened a collection of 1,000 fragments, present in the Maybridge Ro3 library, for whole-cell activity against Mycobacterium tuberculosis. Twenty-nine primary hits showed dose-dependent growth inhibition equal to or better than that of pyrazinamide. The most potent hit, indole propionic acid [IPA; 3-(1H-indol-3-yl)propanoic acid], a metabolite produced by the gut microbiota, was profiled in vivo. The molecule was well tolerated in mice and showed adequate pharmacokinetic properties. In a mouse model of acute M. tuberculosis infection, IPA reduced the bacterial load in the spleen 7-fold. Our results suggest that IPA should be evaluated as an add-on to current regimens and that fragment libraries should be further explored to identify antimycobacterial lead candidates. American Society for Microbiology 2018-02-23 /pmc/articles/PMC5826148/ /pubmed/29229639 http://dx.doi.org/10.1128/AAC.01571-17 Text en Copyright © 2018 Negatu et al. https://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Experimental Therapeutics Negatu, Dereje A. Liu, Joe J. J. Zimmerman, Matthew Kaya, Firat Dartois, Véronique Aldrich, Courtney C. Gengenbacher, Martin Dick, Thomas Whole-Cell Screen of Fragment Library Identifies Gut Microbiota Metabolite Indole Propionic Acid as Antitubercular |
title | Whole-Cell Screen of Fragment Library Identifies Gut Microbiota Metabolite Indole Propionic Acid as Antitubercular |
title_full | Whole-Cell Screen of Fragment Library Identifies Gut Microbiota Metabolite Indole Propionic Acid as Antitubercular |
title_fullStr | Whole-Cell Screen of Fragment Library Identifies Gut Microbiota Metabolite Indole Propionic Acid as Antitubercular |
title_full_unstemmed | Whole-Cell Screen of Fragment Library Identifies Gut Microbiota Metabolite Indole Propionic Acid as Antitubercular |
title_short | Whole-Cell Screen of Fragment Library Identifies Gut Microbiota Metabolite Indole Propionic Acid as Antitubercular |
title_sort | whole-cell screen of fragment library identifies gut microbiota metabolite indole propionic acid as antitubercular |
topic | Experimental Therapeutics |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5826148/ https://www.ncbi.nlm.nih.gov/pubmed/29229639 http://dx.doi.org/10.1128/AAC.01571-17 |
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