Cargando…
The application of tetracyclineregulated gene expression systems in the validation of novel drug targets in Mycobacterium tuberculosis
Although efforts to identify novel therapies for the treatment of tuberculosis have led to the identification of several promising drug candidates, the identification of high-quality hits from conventional whole-cell screens remains disappointingly low. The elucidation of the genome sequence of Myco...
Autores principales: | , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2015
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4523840/ https://www.ncbi.nlm.nih.gov/pubmed/26300875 http://dx.doi.org/10.3389/fmicb.2015.00812 |
_version_ | 1782384122343194624 |
---|---|
author | Evans, Joanna C. Mizrahi, Valerie |
author_facet | Evans, Joanna C. Mizrahi, Valerie |
author_sort | Evans, Joanna C. |
collection | PubMed |
description | Although efforts to identify novel therapies for the treatment of tuberculosis have led to the identification of several promising drug candidates, the identification of high-quality hits from conventional whole-cell screens remains disappointingly low. The elucidation of the genome sequence of Mycobacterium tuberculosis (Mtb) facilitated a shift to target-based approaches to drug design but these efforts have proven largely unsuccessful. More recently, regulated gene expression systems that enable dose-dependent modulation of gene expression have been applied in target validation to evaluate the requirement of individual genes for the growth of Mtb both in vitro and in vivo. Notably, these systems can also provide a measure of the extent to which putative targets must be depleted in order to manifest a growth inhibitory phenotype. Additionally, the successful implementation of Mtb strains engineered to under-express specific molecular targets in whole-cell screens has enabled the simultaneous identification of cell-permeant inhibitors with defined mechanisms of action. Here, we review the application of tetracycline-regulated gene expression systems in the validation of novel drug targets in Mtb, highlighting both the strengths and limitations associated with this approach to target validation. |
format | Online Article Text |
id | pubmed-4523840 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2015 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-45238402015-08-21 The application of tetracyclineregulated gene expression systems in the validation of novel drug targets in Mycobacterium tuberculosis Evans, Joanna C. Mizrahi, Valerie Front Microbiol Microbiology Although efforts to identify novel therapies for the treatment of tuberculosis have led to the identification of several promising drug candidates, the identification of high-quality hits from conventional whole-cell screens remains disappointingly low. The elucidation of the genome sequence of Mycobacterium tuberculosis (Mtb) facilitated a shift to target-based approaches to drug design but these efforts have proven largely unsuccessful. More recently, regulated gene expression systems that enable dose-dependent modulation of gene expression have been applied in target validation to evaluate the requirement of individual genes for the growth of Mtb both in vitro and in vivo. Notably, these systems can also provide a measure of the extent to which putative targets must be depleted in order to manifest a growth inhibitory phenotype. Additionally, the successful implementation of Mtb strains engineered to under-express specific molecular targets in whole-cell screens has enabled the simultaneous identification of cell-permeant inhibitors with defined mechanisms of action. Here, we review the application of tetracycline-regulated gene expression systems in the validation of novel drug targets in Mtb, highlighting both the strengths and limitations associated with this approach to target validation. Frontiers Media S.A. 2015-08-04 /pmc/articles/PMC4523840/ /pubmed/26300875 http://dx.doi.org/10.3389/fmicb.2015.00812 Text en Copyright © 2015 Evans and Mizrahi. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Microbiology Evans, Joanna C. Mizrahi, Valerie The application of tetracyclineregulated gene expression systems in the validation of novel drug targets in Mycobacterium tuberculosis |
title | The application of tetracyclineregulated gene expression systems in the validation of novel drug targets in Mycobacterium tuberculosis |
title_full | The application of tetracyclineregulated gene expression systems in the validation of novel drug targets in Mycobacterium tuberculosis |
title_fullStr | The application of tetracyclineregulated gene expression systems in the validation of novel drug targets in Mycobacterium tuberculosis |
title_full_unstemmed | The application of tetracyclineregulated gene expression systems in the validation of novel drug targets in Mycobacterium tuberculosis |
title_short | The application of tetracyclineregulated gene expression systems in the validation of novel drug targets in Mycobacterium tuberculosis |
title_sort | application of tetracyclineregulated gene expression systems in the validation of novel drug targets in mycobacterium tuberculosis |
topic | Microbiology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4523840/ https://www.ncbi.nlm.nih.gov/pubmed/26300875 http://dx.doi.org/10.3389/fmicb.2015.00812 |
work_keys_str_mv | AT evansjoannac theapplicationoftetracyclineregulatedgeneexpressionsystemsinthevalidationofnoveldrugtargetsinmycobacteriumtuberculosis AT mizrahivalerie theapplicationoftetracyclineregulatedgeneexpressionsystemsinthevalidationofnoveldrugtargetsinmycobacteriumtuberculosis AT evansjoannac applicationoftetracyclineregulatedgeneexpressionsystemsinthevalidationofnoveldrugtargetsinmycobacteriumtuberculosis AT mizrahivalerie applicationoftetracyclineregulatedgeneexpressionsystemsinthevalidationofnoveldrugtargetsinmycobacteriumtuberculosis |