Author:
Tükenmez Hasan,Sarkar Souvik,Anoosheh Saber,Kruchanova Anastasiia,Edström Isabel,Harrison Gregory A.,Stallings Christina L.,Almqvist Fredrik,Larsson Christer
Abstract
AbstractTuberculosis, caused by Mycobacterium tuberculosis (Mtb), is a major health threat listed among the top 10 causes of death worldwide. Treatment of multidrug-resistant Mtb requires use of additional second-line drugs that prolong the treatment process and result in higher death rates. Our team previously identified a 2-pyridone molecule (C10) that blocks tolerance to the first-line drug isoniazid at C10 concentrations that do not inhibit bacterial growth. Here, we discovered that the genes rv3160c and rv3161c are highly induced by C10, which led us to investigate them as potential targets. We show that Rv3160c acts as a TetR-like transcriptional repressor binding to a palindromic sequence located in the rv3161c promoter. We also demonstrate that C10 interacts with Rv3160c, inhibiting its binding to DNA. We deleted the rv3161c gene, coding for a putative oxygenase, to investigate its role in drug and stress sensitivity as well as C10 activity. This Δrv3161c strain was more tolerant to isoniazid and lysozyme than wild type Mtb. However, this tolerance could still be blocked by C10, suggesting that C10 functions independently of Rv3161c to influence isoniazid and lysozyme sensitivity.
Funder
National Science Foundation Graduate Research Fellowship
National Institute of General Medical Sciences Cell and Molecular Biology Training Grant
National Institutes of Health
Familjen Erling-Perssons Stiftelse
Burroughs Wellcome Fund
Kempestiftelserna
Vetenskapsrådet
Åke Wilton's Fund
Umea University
Publisher
Springer Science and Business Media LLC
Cited by
8 articles.
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