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Tudo et al_FMC_Accepted manuscript 2010.pdf (686 kB)

Examining the basis of isoniazid tolerance in nonreplicating Mycobacterium tuberculosis using transcriptional profiling

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posted on 2023-06-07, 15:34 authored by Griselda Tudo, Ken Laing, Denis A Mitchison, Philip D Butcher, Simon WaddellSimon Waddell
Background: Understanding how growth state influences Mycobacterium tuberculosis responses to antibiotic exposure provides a window into drug action during patient chemotherapy. In this article, we describe the transcriptional programs mediated by isoniazid (INH) during the transition from log-phase to nonreplicating bacilli, from INH-sensitive to INH-tolerant bacilli respectively, using the Wayne model. Results: INH treatment did not elicit a transcriptional response from nonreplicating bacteria under microarophilic conditions (NRP2), unlike the induction of a robust and well-characterized INH signature in log-phase bacilli. Conclusion: The differential regulation (between drug-free NRP2 and log-phase bacilli) of genes directly implicated in INH resistance could not account for the abrogation of INH killing in nongrowing bacilli. Thus, factors affecting the requirement for mycolic acids and the redox status of bacilli are likely responsible for the reduction in INH efficacy. We speculate on additional mechanisms revealed by transcriptome analysis that might account for INH tolerance.

History

Publication status

  • Published

File Version

  • Accepted version

Journal

Future Medicinal Chemistry

ISSN

1756-8919

Publisher

Future Science

Issue

8

Volume

2

Page range

1371-1383

Department affiliated with

  • Clinical and Experimental Medicine Publications

Notes

Future Medicinal Chemistry has a one year embargo on uploading the full text from the date of publication

Full text available

  • Yes

Peer reviewed?

  • Yes

Legacy Posted Date

2010-10-26

First Open Access (FOA) Date

2017-01-23

First Compliant Deposit (FCD) Date

2017-01-23

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