A novel class of antimicrobial drugs selectively targets a Mycobacterium tuberculosis PE-PGRS protein

Autor: Hoonhee Seo, Sukyung Kim, Hafij Al Mahmud, Md Imtiazul Islam, Youjin Yoon, Hyun-Deuk Cho, Kung-Woo Nam, Jiwon Choi, Young Sig Gil, Byung-Eui Lee, Ho-Yeon Song
Jazyk: angličtina
Rok vydání: 2022
Předmět:
Zdroj: PLoS Biology, Vol 20, Iss 5 (2022)
Druh dokumentu: article
ISSN: 1544-9173
1545-7885
Popis: 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. This study identifies a new class of PP derivatives as Mycobacterium tuberculosis-targeting antimicrobials with microbiome-safe properties that do not disrupt normal flora, making them a promising candidate for the treatment of drug-resistant tuberculosis.
Databáze: Directory of Open Access Journals
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