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Conditional Silencing by CRISPRi Reveals the Role of DNA Gyrase in Formation of Drug-Tolerant Persister Population in Mycobacterium tuberculosis
Drug tolerance in mycobacterial pathogens is a global concern. Fluoroquinolone (FQ) treatment is widely used for induction of persisters in bacteria. Although FQs that target DNA gyrase are currently used as second-line anti-tuberculosis (TB) drugs, little is known about their impact on Mycobacteriu...
Autores principales: | , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6443821/ https://www.ncbi.nlm.nih.gov/pubmed/30972304 http://dx.doi.org/10.3389/fcimb.2019.00070 |
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author | Choudhary, Eira Sharma, Rishabh Kumar, Yashwant Agarwal, Nisheeth |
author_facet | Choudhary, Eira Sharma, Rishabh Kumar, Yashwant Agarwal, Nisheeth |
author_sort | Choudhary, Eira |
collection | PubMed |
description | Drug tolerance in mycobacterial pathogens is a global concern. Fluoroquinolone (FQ) treatment is widely used for induction of persisters in bacteria. Although FQs that target DNA gyrase are currently used as second-line anti-tuberculosis (TB) drugs, little is known about their impact on Mycobacterium tuberculosis (Mtb) persister formation. Here we explored the CRISPRi-based genetic repression for better understanding the effect of DNA gyrase depletion on Mtb physiology and response to anti-TB drugs. We find that suppression of DNA gyrase drastically affects intra- and extracellular growth of Mtb. Interestingly, gyrase depletion in Mtb leads to activation of RecA/LexA-mediated SOS response and drug tolerance via induction of persister subpopulation. Chemical inhibition of RecA in gyrase-depleted bacteria results in reversion of persister phenotype and better killing by antibiotics. This study provides evidence that inhibition of SOS response can be advantageous in improving the efficacy of anti-TB drugs and shortening the duration of current TB treatment. |
format | Online Article Text |
id | pubmed-6443821 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-64438212019-04-10 Conditional Silencing by CRISPRi Reveals the Role of DNA Gyrase in Formation of Drug-Tolerant Persister Population in Mycobacterium tuberculosis Choudhary, Eira Sharma, Rishabh Kumar, Yashwant Agarwal, Nisheeth Front Cell Infect Microbiol Cellular and Infection Microbiology Drug tolerance in mycobacterial pathogens is a global concern. Fluoroquinolone (FQ) treatment is widely used for induction of persisters in bacteria. Although FQs that target DNA gyrase are currently used as second-line anti-tuberculosis (TB) drugs, little is known about their impact on Mycobacterium tuberculosis (Mtb) persister formation. Here we explored the CRISPRi-based genetic repression for better understanding the effect of DNA gyrase depletion on Mtb physiology and response to anti-TB drugs. We find that suppression of DNA gyrase drastically affects intra- and extracellular growth of Mtb. Interestingly, gyrase depletion in Mtb leads to activation of RecA/LexA-mediated SOS response and drug tolerance via induction of persister subpopulation. Chemical inhibition of RecA in gyrase-depleted bacteria results in reversion of persister phenotype and better killing by antibiotics. This study provides evidence that inhibition of SOS response can be advantageous in improving the efficacy of anti-TB drugs and shortening the duration of current TB treatment. Frontiers Media S.A. 2019-03-26 /pmc/articles/PMC6443821/ /pubmed/30972304 http://dx.doi.org/10.3389/fcimb.2019.00070 Text en Copyright © 2019 Choudhary, Sharma, Kumar and Agarwal. 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) and the copyright owner(s) 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 | Cellular and Infection Microbiology Choudhary, Eira Sharma, Rishabh Kumar, Yashwant Agarwal, Nisheeth Conditional Silencing by CRISPRi Reveals the Role of DNA Gyrase in Formation of Drug-Tolerant Persister Population in Mycobacterium tuberculosis |
title | Conditional Silencing by CRISPRi Reveals the Role of DNA Gyrase in Formation of Drug-Tolerant Persister Population in Mycobacterium tuberculosis |
title_full | Conditional Silencing by CRISPRi Reveals the Role of DNA Gyrase in Formation of Drug-Tolerant Persister Population in Mycobacterium tuberculosis |
title_fullStr | Conditional Silencing by CRISPRi Reveals the Role of DNA Gyrase in Formation of Drug-Tolerant Persister Population in Mycobacterium tuberculosis |
title_full_unstemmed | Conditional Silencing by CRISPRi Reveals the Role of DNA Gyrase in Formation of Drug-Tolerant Persister Population in Mycobacterium tuberculosis |
title_short | Conditional Silencing by CRISPRi Reveals the Role of DNA Gyrase in Formation of Drug-Tolerant Persister Population in Mycobacterium tuberculosis |
title_sort | conditional silencing by crispri reveals the role of dna gyrase in formation of drug-tolerant persister population in mycobacterium tuberculosis |
topic | Cellular and Infection Microbiology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6443821/ https://www.ncbi.nlm.nih.gov/pubmed/30972304 http://dx.doi.org/10.3389/fcimb.2019.00070 |
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