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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...

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Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2022
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.
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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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