Transcriptomic Profile of Mycobacterium smegmatis in Response to an Imidazo[1,2-b][1,2,4,5]tetrazine Reveals Its Possible Impact on Iron Metabolism
Tuberculosis (TB), caused by the Mycobacterium tuberculosis complex bacteria, is one of the most pressing health problems. The development of new drugs and new therapeutic regimens effective against the pathogen is one of the greatest challenges in the way of tuberculosis control. Imidazo[1,2-b][1,2...
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doaj-56fe4d7741e348d6b8b3a7799460730b2021-08-04T07:23:41ZengFrontiers Media S.A.Frontiers in Microbiology1664-302X2021-08-011210.3389/fmicb.2021.724042724042Transcriptomic Profile of Mycobacterium smegmatis in Response to an Imidazo[1,2-b][1,2,4,5]tetrazine Reveals Its Possible Impact on Iron MetabolismAleksey A. Vatlin0Aleksey A. Vatlin1Egor A. Shitikov2Mohd Shahbaaz3Dmitry A. Bespiatykh4Ksenia M. Klimina5Ksenia M. Klimina6Alan Christoffels7Valery N. Danilenko8Dmitry A. Maslov9Laboratory of Bacterial Genetics, Vavilov Institute of General Genetics Russian Academy of Sciences, Moscow, RussiaPeoples’ Friendship University of Russia (RUDN University), Moscow, RussiaDepartment of Molecular Biology and Genetics, Federal Research and Clinical Center of Physical-Chemical Medicine of Federal Medical Biological Agency, Moscow, RussiaSouth Africa Medical Research Council Bioinformatics Unit, South African National Bioinformatics Institute, University of the Western Cape, Cape Town, South AfricaDepartment of Molecular Biology and Genetics, Federal Research and Clinical Center of Physical-Chemical Medicine of Federal Medical Biological Agency, Moscow, RussiaLaboratory of Bacterial Genetics, Vavilov Institute of General Genetics Russian Academy of Sciences, Moscow, RussiaDepartment of Molecular Biology and Genetics, Federal Research and Clinical Center of Physical-Chemical Medicine of Federal Medical Biological Agency, Moscow, RussiaSouth Africa Medical Research Council Bioinformatics Unit, South African National Bioinformatics Institute, University of the Western Cape, Cape Town, South AfricaLaboratory of Bacterial Genetics, Vavilov Institute of General Genetics Russian Academy of Sciences, Moscow, RussiaLaboratory of Bacterial Genetics, Vavilov Institute of General Genetics Russian Academy of Sciences, Moscow, RussiaTuberculosis (TB), caused by the Mycobacterium tuberculosis complex bacteria, is one of the most pressing health problems. The development of new drugs and new therapeutic regimens effective against the pathogen is one of the greatest challenges in the way of tuberculosis control. Imidazo[1,2-b][1,2,4,5]tetrazines have shown promising activity against M. tuberculosis and M. smegmatis strains. Mutations in MSMEG_1380 lead to mmpS5–mmpL5 operon overexpression, which provides M. smegmatis with efflux-mediated resistance to imidazo[1,2-b][1,2,4,5]tetrazines, but the exact mechanism of action of these compounds remains unknown. To assess the mode of action of imidazo[1,2-b][1,2,4,5]tetrazines, we analyzed the transcriptomic response of M. smegmatis to three different concentrations of 3a compound: 1/8×, 1/4×, and 1/2× MIC. Six groups of genes responsible for siderophore synthesis and transport were upregulated in a dose-dependent manner, while virtual docking revealed proteins involved in siderophore synthesis as possible targets for 3a. Thus, we suggest that imidazo[1,2-b][1,2,4,5]tetrazines may affect mycobacterial iron metabolism.https://www.frontiersin.org/articles/10.3389/fmicb.2021.724042/fullMycobacteriumdrug resistanceimidazo[12-b][124 |
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DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Aleksey A. Vatlin Aleksey A. Vatlin Egor A. Shitikov Mohd Shahbaaz Dmitry A. Bespiatykh Ksenia M. Klimina Ksenia M. Klimina Alan Christoffels Valery N. Danilenko Dmitry A. Maslov |
spellingShingle |
Aleksey A. Vatlin Aleksey A. Vatlin Egor A. Shitikov Mohd Shahbaaz Dmitry A. Bespiatykh Ksenia M. Klimina Ksenia M. Klimina Alan Christoffels Valery N. Danilenko Dmitry A. Maslov Transcriptomic Profile of Mycobacterium smegmatis in Response to an Imidazo[1,2-b][1,2,4,5]tetrazine Reveals Its Possible Impact on Iron Metabolism Frontiers in Microbiology Mycobacterium drug resistance imidazo[1 2-b][1 2 4 |
author_facet |
Aleksey A. Vatlin Aleksey A. Vatlin Egor A. Shitikov Mohd Shahbaaz Dmitry A. Bespiatykh Ksenia M. Klimina Ksenia M. Klimina Alan Christoffels Valery N. Danilenko Dmitry A. Maslov |
author_sort |
Aleksey A. Vatlin |
title |
Transcriptomic Profile of Mycobacterium smegmatis in Response to an Imidazo[1,2-b][1,2,4,5]tetrazine Reveals Its Possible Impact on Iron Metabolism |
title_short |
Transcriptomic Profile of Mycobacterium smegmatis in Response to an Imidazo[1,2-b][1,2,4,5]tetrazine Reveals Its Possible Impact on Iron Metabolism |
title_full |
Transcriptomic Profile of Mycobacterium smegmatis in Response to an Imidazo[1,2-b][1,2,4,5]tetrazine Reveals Its Possible Impact on Iron Metabolism |
title_fullStr |
Transcriptomic Profile of Mycobacterium smegmatis in Response to an Imidazo[1,2-b][1,2,4,5]tetrazine Reveals Its Possible Impact on Iron Metabolism |
title_full_unstemmed |
Transcriptomic Profile of Mycobacterium smegmatis in Response to an Imidazo[1,2-b][1,2,4,5]tetrazine Reveals Its Possible Impact on Iron Metabolism |
title_sort |
transcriptomic profile of mycobacterium smegmatis in response to an imidazo[1,2-b][1,2,4,5]tetrazine reveals its possible impact on iron metabolism |
publisher |
Frontiers Media S.A. |
series |
Frontiers in Microbiology |
issn |
1664-302X |
publishDate |
2021-08-01 |
description |
Tuberculosis (TB), caused by the Mycobacterium tuberculosis complex bacteria, is one of the most pressing health problems. The development of new drugs and new therapeutic regimens effective against the pathogen is one of the greatest challenges in the way of tuberculosis control. Imidazo[1,2-b][1,2,4,5]tetrazines have shown promising activity against M. tuberculosis and M. smegmatis strains. Mutations in MSMEG_1380 lead to mmpS5–mmpL5 operon overexpression, which provides M. smegmatis with efflux-mediated resistance to imidazo[1,2-b][1,2,4,5]tetrazines, but the exact mechanism of action of these compounds remains unknown. To assess the mode of action of imidazo[1,2-b][1,2,4,5]tetrazines, we analyzed the transcriptomic response of M. smegmatis to three different concentrations of 3a compound: 1/8×, 1/4×, and 1/2× MIC. Six groups of genes responsible for siderophore synthesis and transport were upregulated in a dose-dependent manner, while virtual docking revealed proteins involved in siderophore synthesis as possible targets for 3a. Thus, we suggest that imidazo[1,2-b][1,2,4,5]tetrazines may affect mycobacterial iron metabolism. |
topic |
Mycobacterium drug resistance imidazo[1 2-b][1 2 4 |
url |
https://www.frontiersin.org/articles/10.3389/fmicb.2021.724042/full |
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