TY - JOUR
T1 - Mycobacterium tuberculosis Rv3160c is a TetR-like transcriptional repressor that regulates expression of the putative oxygenase Rv3161c
AU - Tükenmez, Hasan
AU - Sarkar, Souvik
AU - Anoosheh, Saber
AU - Kruchanova, Anastasiia
AU - Edström, Isabel
AU - Harrison, Gregory A.
AU - Stallings, Christina L.
AU - Almqvist, Fredrik
AU - Larsson, Christer
N1 - Funding Information:
This project has been supported under the framework of the JPIAMR – Joint Programming Initiative on Antimicrobial Resistance. C.L. is supported by the Kempe Foundation [SMK-1648] and the Åke Wilton’s Fund [FS 2.1.6-1577-17]. F.A. and C.L.S. are supported by the National Institutes of Health Grant [R01 AI134847] and the Erling-Persson Family Foundation [P20-00473]. F.A. is supported by the Swedish Research Council (JPIAMR) [2018-00969] and the Kempe Foundation [SMK-1755]. C.L.S. is supported by the Burroughs Welcome Fund Investigators in the Pathogenesis of Infectious Disease [1016717]. G.A.H. is supported by the National Science Foundation Graduate Research Fellowship [DGE-1745038] and the National Institute of General Medical Sciences Cell and Molecular Biology Training Grant [GM007067]. The personnel of the Protein Expertise Platform (PEP) at the Chemical Biological Center (KBC) at Umeå University is acknowledged for their skills and support in protein purification.
Publisher Copyright:
© 2021, The Author(s).
PY - 2021/12
Y1 - 2021/12
N2 - Tuberculosis, 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.
AB - Tuberculosis, 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.
UR - http://www.scopus.com/inward/record.url?scp=85100124969&partnerID=8YFLogxK
U2 - 10.1038/s41598-021-81104-y
DO - 10.1038/s41598-021-81104-y
M3 - Article
C2 - 33452380
AN - SCOPUS:85100124969
SN - 2045-2322
VL - 11
JO - Scientific reports
JF - Scientific reports
IS - 1
M1 - 1523
ER -