In:
PLOS Biology, Public Library of Science (PLoS), Vol. 20, No. 5 ( 2022-5-31), p. e3001648-
Abstract:
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.
Type of Medium:
Online Resource
ISSN:
1545-7885
DOI:
10.1371/journal.pbio.3001648
DOI:
10.1371/journal.pbio.3001648.g001
DOI:
10.1371/journal.pbio.3001648.g002
DOI:
10.1371/journal.pbio.3001648.g003
DOI:
10.1371/journal.pbio.3001648.g004
DOI:
10.1371/journal.pbio.3001648.g005
DOI:
10.1371/journal.pbio.3001648.g006
DOI:
10.1371/journal.pbio.3001648.g007
DOI:
10.1371/journal.pbio.3001648.t001
DOI:
10.1371/journal.pbio.3001648.t002
DOI:
10.1371/journal.pbio.3001648.t003
DOI:
10.1371/journal.pbio.3001648.t004
DOI:
10.1371/journal.pbio.3001648.s001
DOI:
10.1371/journal.pbio.3001648.s002
DOI:
10.1371/journal.pbio.3001648.s003
DOI:
10.1371/journal.pbio.3001648.s004
DOI:
10.1371/journal.pbio.3001648.s005
DOI:
10.1371/journal.pbio.3001648.s006
DOI:
10.1371/journal.pbio.3001648.s007
DOI:
10.1371/journal.pbio.3001648.s008
DOI:
10.1371/journal.pbio.3001648.s009
DOI:
10.1371/journal.pbio.3001648.s010
DOI:
10.1371/journal.pbio.3001648.s011
DOI:
10.1371/journal.pbio.3001648.s012
DOI:
10.1371/journal.pbio.3001648.s013
DOI:
10.1371/journal.pbio.3001648.s014
DOI:
10.1371/journal.pbio.3001648.s015
DOI:
10.1371/journal.pbio.3001648.s016
DOI:
10.1371/journal.pbio.3001648.s017
DOI:
10.1371/journal.pbio.3001648.s018
Language:
English
Publisher:
Public Library of Science (PLoS)
Publication Date:
2022
detail.hit.zdb_id:
2126773-X
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