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Chemical Exploration of a Highly Selective Scaffold with Activity against Intracellular Mycobacterium tuberculosis
We previously identified a phenylthiourea series with activity against intracellular Mycobacterium tuberculosis using a high-throughput, high-content assay. We conducted a catalog structure-activity relationship study with a collection of 35 analogs. We identified several thiourea derivatives with e...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Society for Microbiology
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9241686/ https://www.ncbi.nlm.nih.gov/pubmed/35612308 http://dx.doi.org/10.1128/spectrum.01161-22 |
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author | Njikan, Samuel Ahmed, Sara Manning, Alyssa Awasthi, Divya Ovechkina, Yulia Chowdhury, Sultan Butts, Arielle Parish, Tanya |
author_facet | Njikan, Samuel Ahmed, Sara Manning, Alyssa Awasthi, Divya Ovechkina, Yulia Chowdhury, Sultan Butts, Arielle Parish, Tanya |
author_sort | Njikan, Samuel |
collection | PubMed |
description | We previously identified a phenylthiourea series with activity against intracellular Mycobacterium tuberculosis using a high-throughput, high-content assay. We conducted a catalog structure-activity relationship study with a collection of 35 analogs. We identified several thiourea derivatives with excellent potency against intracellular bacteria and good selectivity over eukaryotic cells. Compounds had much lower activity against extracellular bacteria, which was not increased by using cholesterol as the sole carbon source. Compounds were equally active against strains with mutations in QcrB or MmpL3, thereby excluding common, promiscuous targets as the mode of action. The phenylthiourea series represents a good starting point for further exploration to develop novel antitubercular agents. IMPORTANCE Mycobacterium tuberculosis is responsible for the highest number of deaths from a bacterial pathogen, with >1.5 million in 2020. M. tuberculosis is a sophisticated pathogen that can replicate inside immune cells. There is an urgent need for new drugs to combat M. tuberculosis and to shorten therapy from 6 to 24 months. We have identified a series of molecules that inhibit the growth of M. tuberculosis inside macrophages; we tested a number of derivatives to link structural features to biological activity. The compounds are likely to have novel mechanism of action and so could be developed as new agents for drug-resistant tuberculosis. |
format | Online Article Text |
id | pubmed-9241686 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | American Society for Microbiology |
record_format | MEDLINE/PubMed |
spelling | pubmed-92416862022-06-30 Chemical Exploration of a Highly Selective Scaffold with Activity against Intracellular Mycobacterium tuberculosis Njikan, Samuel Ahmed, Sara Manning, Alyssa Awasthi, Divya Ovechkina, Yulia Chowdhury, Sultan Butts, Arielle Parish, Tanya Microbiol Spectr Research Article We previously identified a phenylthiourea series with activity against intracellular Mycobacterium tuberculosis using a high-throughput, high-content assay. We conducted a catalog structure-activity relationship study with a collection of 35 analogs. We identified several thiourea derivatives with excellent potency against intracellular bacteria and good selectivity over eukaryotic cells. Compounds had much lower activity against extracellular bacteria, which was not increased by using cholesterol as the sole carbon source. Compounds were equally active against strains with mutations in QcrB or MmpL3, thereby excluding common, promiscuous targets as the mode of action. The phenylthiourea series represents a good starting point for further exploration to develop novel antitubercular agents. IMPORTANCE Mycobacterium tuberculosis is responsible for the highest number of deaths from a bacterial pathogen, with >1.5 million in 2020. M. tuberculosis is a sophisticated pathogen that can replicate inside immune cells. There is an urgent need for new drugs to combat M. tuberculosis and to shorten therapy from 6 to 24 months. We have identified a series of molecules that inhibit the growth of M. tuberculosis inside macrophages; we tested a number of derivatives to link structural features to biological activity. The compounds are likely to have novel mechanism of action and so could be developed as new agents for drug-resistant tuberculosis. American Society for Microbiology 2022-05-25 /pmc/articles/PMC9241686/ /pubmed/35612308 http://dx.doi.org/10.1128/spectrum.01161-22 Text en Copyright © 2022 Njikan 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 | Research Article Njikan, Samuel Ahmed, Sara Manning, Alyssa Awasthi, Divya Ovechkina, Yulia Chowdhury, Sultan Butts, Arielle Parish, Tanya Chemical Exploration of a Highly Selective Scaffold with Activity against Intracellular Mycobacterium tuberculosis |
title | Chemical Exploration of a Highly Selective Scaffold with Activity against Intracellular Mycobacterium tuberculosis |
title_full | Chemical Exploration of a Highly Selective Scaffold with Activity against Intracellular Mycobacterium tuberculosis |
title_fullStr | Chemical Exploration of a Highly Selective Scaffold with Activity against Intracellular Mycobacterium tuberculosis |
title_full_unstemmed | Chemical Exploration of a Highly Selective Scaffold with Activity against Intracellular Mycobacterium tuberculosis |
title_short | Chemical Exploration of a Highly Selective Scaffold with Activity against Intracellular Mycobacterium tuberculosis |
title_sort | chemical exploration of a highly selective scaffold with activity against intracellular mycobacterium tuberculosis |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9241686/ https://www.ncbi.nlm.nih.gov/pubmed/35612308 http://dx.doi.org/10.1128/spectrum.01161-22 |
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