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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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Autores principales: Vatlin, Aleksey A., Shitikov, Egor A., Shahbaaz, Mohd, Bespiatykh, Dmitry A., Klimina, Ksenia M., Christoffels, Alan, Danilenko, Valery N., Maslov, Dmitry A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8371482/
https://www.ncbi.nlm.nih.gov/pubmed/34421882
http://dx.doi.org/10.3389/fmicb.2021.724042
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author Vatlin, Aleksey A.
Shitikov, Egor A.
Shahbaaz, Mohd
Bespiatykh, Dmitry A.
Klimina, Ksenia M.
Christoffels, Alan
Danilenko, Valery N.
Maslov, Dmitry A.
author_facet Vatlin, Aleksey A.
Shitikov, Egor A.
Shahbaaz, Mohd
Bespiatykh, Dmitry A.
Klimina, Ksenia M.
Christoffels, Alan
Danilenko, Valery N.
Maslov, Dmitry A.
author_sort Vatlin, Aleksey A.
collection PubMed
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.
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spelling pubmed-83714822021-08-19 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 Vatlin, Aleksey A. Shitikov, Egor A. Shahbaaz, Mohd Bespiatykh, Dmitry A. Klimina, Ksenia M. Christoffels, Alan Danilenko, Valery N. Maslov, Dmitry A. Front Microbiol Microbiology 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. Frontiers Media S.A. 2021-08-04 /pmc/articles/PMC8371482/ /pubmed/34421882 http://dx.doi.org/10.3389/fmicb.2021.724042 Text en Copyright © 2021 Vatlin, Shitikov, Shahbaaz, Bespiatykh, Klimina, Christoffels, Danilenko and Maslov. https://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 Microbiology
Vatlin, Aleksey A.
Shitikov, Egor A.
Shahbaaz, Mohd
Bespiatykh, Dmitry A.
Klimina, Ksenia M.
Christoffels, Alan
Danilenko, Valery N.
Maslov, Dmitry A.
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 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_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_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
topic Microbiology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8371482/
https://www.ncbi.nlm.nih.gov/pubmed/34421882
http://dx.doi.org/10.3389/fmicb.2021.724042
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