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A novel class of antimicrobial drugs selectively targets a Mycobacterium tuberculosis PE-PGRS protein
The continued spread of drug-resistant tuberculosis is one of the most pressing and complex challenges facing tuberculosis management worldwide. Therefore, developing a new class of drugs is necessary and urgently needed to cope with the increasing threat of drug-resistant tuberculosis. This study a...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9154192/ https://www.ncbi.nlm.nih.gov/pubmed/35639773 http://dx.doi.org/10.1371/journal.pbio.3001648 |
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author | Seo, Hoonhee Kim, Sukyung Mahmud, Hafij Al Islam, Md Imtiazul Yoon, Youjin Cho, Hyun-Deuk Nam, Kung-Woo Choi, Jiwon Gil, Young Sig Lee, Byung-Eui Song, Ho-Yeon |
author_facet | Seo, Hoonhee Kim, Sukyung Mahmud, Hafij Al Islam, Md Imtiazul Yoon, Youjin Cho, Hyun-Deuk Nam, Kung-Woo Choi, Jiwon Gil, Young Sig Lee, Byung-Eui Song, Ho-Yeon |
author_sort | Seo, Hoonhee |
collection | PubMed |
description | The continued spread of drug-resistant tuberculosis is one of the most pressing and complex challenges facing tuberculosis management worldwide. Therefore, developing a new class of drugs is necessary and urgently needed to cope with the increasing threat of drug-resistant tuberculosis. This study aims to discover a potential new class of tuberculosis drug candidates different from existing tuberculosis drugs. By screening a library of compounds, methyl (S)-1-((3-alkoxy-6,7-dimethoxyphenanthren-9-yl)methyl)-5-oxopyrrolidine-2-carboxylate (PP) derivatives with antitubercular activity were discovered. MIC ranges for PP1S, PP2S, and PP3S against clinically isolated drug-resistant Mycobacterium tuberculosis strains were 0.78 to 3.13, 0.19 to 1.56, and 0.78 to 6.25 μg/ml, respectively. PPs demonstrated antitubercular activities in macrophage and tuberculosis mouse models, showing no detectable toxicity in all assays tested. PPs specifically inhibited M. tuberculosis without significantly changing the intestinal microbiome in mice. Mutants selected in vitro suggest that the drug targets the PE-PGRS57, which has been found only in the genomes of the M. tuberculosis complex, highlighting the specificity and safety potency of this compound. As PPs show an excellent safety profile and highly selective toxicity specific to M. tuberculosis, PPs are considered a promising new candidate for the treatment of drug-resistant tuberculosis while maintaining microbiome homeostasis. |
format | Online Article Text |
id | pubmed-9154192 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-91541922022-06-01 A novel class of antimicrobial drugs selectively targets a Mycobacterium tuberculosis PE-PGRS protein Seo, Hoonhee Kim, Sukyung Mahmud, Hafij Al Islam, Md Imtiazul Yoon, Youjin Cho, Hyun-Deuk Nam, Kung-Woo Choi, Jiwon Gil, Young Sig Lee, Byung-Eui Song, Ho-Yeon PLoS Biol Research Article The continued spread of drug-resistant tuberculosis is one of the most pressing and complex challenges facing tuberculosis management worldwide. Therefore, developing a new class of drugs is necessary and urgently needed to cope with the increasing threat of drug-resistant tuberculosis. This study aims to discover a potential new class of tuberculosis drug candidates different from existing tuberculosis drugs. By screening a library of compounds, methyl (S)-1-((3-alkoxy-6,7-dimethoxyphenanthren-9-yl)methyl)-5-oxopyrrolidine-2-carboxylate (PP) derivatives with antitubercular activity were discovered. MIC ranges for PP1S, PP2S, and PP3S against clinically isolated drug-resistant Mycobacterium tuberculosis strains were 0.78 to 3.13, 0.19 to 1.56, and 0.78 to 6.25 μg/ml, respectively. PPs demonstrated antitubercular activities in macrophage and tuberculosis mouse models, showing no detectable toxicity in all assays tested. PPs specifically inhibited M. tuberculosis without significantly changing the intestinal microbiome in mice. Mutants selected in vitro suggest that the drug targets the PE-PGRS57, which has been found only in the genomes of the M. tuberculosis complex, highlighting the specificity and safety potency of this compound. As PPs show an excellent safety profile and highly selective toxicity specific to M. tuberculosis, PPs are considered a promising new candidate for the treatment of drug-resistant tuberculosis while maintaining microbiome homeostasis. Public Library of Science 2022-05-31 /pmc/articles/PMC9154192/ /pubmed/35639773 http://dx.doi.org/10.1371/journal.pbio.3001648 Text en © 2022 Seo et al https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
spellingShingle | Research Article Seo, Hoonhee Kim, Sukyung Mahmud, Hafij Al Islam, Md Imtiazul Yoon, Youjin Cho, Hyun-Deuk Nam, Kung-Woo Choi, Jiwon Gil, Young Sig Lee, Byung-Eui Song, Ho-Yeon A novel class of antimicrobial drugs selectively targets a Mycobacterium tuberculosis PE-PGRS protein |
title | A novel class of antimicrobial drugs selectively targets a Mycobacterium tuberculosis PE-PGRS protein |
title_full | A novel class of antimicrobial drugs selectively targets a Mycobacterium tuberculosis PE-PGRS protein |
title_fullStr | A novel class of antimicrobial drugs selectively targets a Mycobacterium tuberculosis PE-PGRS protein |
title_full_unstemmed | A novel class of antimicrobial drugs selectively targets a Mycobacterium tuberculosis PE-PGRS protein |
title_short | A novel class of antimicrobial drugs selectively targets a Mycobacterium tuberculosis PE-PGRS protein |
title_sort | novel class of antimicrobial drugs selectively targets a mycobacterium tuberculosis pe-pgrs protein |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9154192/ https://www.ncbi.nlm.nih.gov/pubmed/35639773 http://dx.doi.org/10.1371/journal.pbio.3001648 |
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