AUTHOR=Vatlin Aleksey A. , Shitikov Egor A. , Shahbaaz Mohd , Bespiatykh Dmitry A. , Klimina Ksenia M. , Christoffels Alan , Danilenko Valery N. , Maslov Dmitry A. 

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

JOURNAL=Frontiers in Microbiology

VOLUME=12

YEAR=2021

URL=https://www.frontiersin.org/journals/microbiology/articles/10.3389/fmicb.2021.724042

DOI=10.3389/fmicb.2021.724042

ISSN=1664-302X

ABSTRACT=<p>Tuberculosis (TB), caused by the <italic>Mycobacterium tuberculosis</italic> 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-<italic>b</italic>][1,2,4,5]tetrazines have shown promising activity against <italic>M. tuberculosis</italic> and <italic>M. smegmatis</italic> strains. Mutations in <italic>MSMEG_1380</italic> lead to <italic>mmpS5–mmpL5</italic> operon overexpression, which provides <italic>M. smegmatis</italic> with efflux-mediated resistance to imidazo[1,2-<italic>b</italic>][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-<italic>b</italic>][1,2,4,5]tetrazines, we analyzed the transcriptomic response of <italic>M. smegmatis</italic> to three different concentrations of <bold>3a</bold> 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 <bold>3a</bold>. Thus, we suggest that imidazo[1,2-<italic>b</italic>][1,2,4,5]tetrazines may affect mycobacterial iron metabolism.</p>