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Hit Compounds and Associated Targets in Intracellular Mycobacterium tuberculosis Tsui, Clement K. M.; Sorrentino, Flavia; Narula, Gagandeep; Mendoza-Losana, Alfonso; del Rio, Ruben Gonzalez; Herrán, Esther Pérez; Lopez, Abraham; Bojang, Adama; Zheng, Xingji; Remuiñán-Blanco, Modesto Jesus; Av-Gay, Yossef

Abstract

Mycobacterium tuberculosis (Mtb), the etiological agent of tuberculosis, is one of the most devastating infectious agents in the world. Chemical-genetic characterization through in vitro evolution combined with whole genome sequencing analysis was used identify novel drug targets and drug resistance genes in Mtb associated with its intracellular growth in human macrophages. We performed a genome analysis of 53 Mtb mutants resistant to 15 different hit compounds. We found nonsynonymous mutations/indels in 30 genes that may be associated with drug resistance acquisitions. Beyond confirming previously identified drug resistance mechanisms such as rpoB and lead targets reported in novel anti-tuberculosis drug screenings such as mmpL3, ethA, and mbtA, we have discovered several unrecognized candidate drug targets including prrB. The exploration of the Mtb chemical mutant genomes could help novel drug discovery and the structural biology of compounds and associated mechanisms of action relevant to tuberculosis treatment.

Item Metadata

Title
Hit Compounds and Associated Targets in Intracellular Mycobacterium tuberculosis
Creator
Tsui, Clement K. M.; Sorrentino, Flavia; Narula, Gagandeep; Mendoza-Losana, Alfonso; del Rio, Ruben Gonzalez; Herrán, Esther Pérez; Lopez, Abraham; Bojang, Adama; Zheng, Xingji; Remuiñán-Blanco, Modesto Jesus; Av-Gay, Yossef
Contributor
University of British Columbia. Life Sciences Institute
Publisher
Multidisciplinary Digital Publishing Institute
Date Issued
2022-07-12
Description
Mycobacterium tuberculosis (Mtb), the etiological agent of tuberculosis, is one of the most devastating infectious agents in the world. Chemical-genetic characterization through in vitro evolution combined with whole genome sequencing analysis was used identify novel drug targets and drug resistance genes in Mtb associated with its intracellular growth in human macrophages. We performed a genome analysis of 53 Mtb mutants resistant to 15 different hit compounds. We found nonsynonymous mutations/indels in 30 genes that may be associated with drug resistance acquisitions. Beyond confirming previously identified drug resistance mechanisms such as rpoB and lead targets reported in novel anti-tuberculosis drug screenings such as mmpL3, ethA, and mbtA, we have discovered several unrecognized candidate drug targets including prrB. The exploration of the Mtb chemical mutant genomes could help novel drug discovery and the structural biology of compounds and associated mechanisms of action relevant to tuberculosis treatment.
Subject
sensitivity; antimicrobial resistance; selection; screening; chemical genetics; bioinformatics; drug discovery; tuberculosis
Genre
Article
Type
Text
Language
eng
Date Available
2023-01-18
Provider
Vancouver : University of British Columbia Library
Rights
CC BY 4.0
DOI
10.14288/1.0423115
URI
http://hdl.handle.net/2429/83677
Affiliation
Medicine, Faculty of; Non UBC; Microbiology and Immunology, Department of
Citation
Molecules 27 (14): 4446 (2022)
Publisher DOI
10.3390/molecules27144446
Peer Review Status
Reviewed
Scholarly Level
Faculty; Researcher; Other
Rights URI
https://creativecommons.org/licenses/by/4.0/
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CC BY 4.0