AUTHOR=Deng Wanyan , Zheng Zengzhang , Chen Yi , Yang Maoyi , Yan Jun , Li Wu , Zeng Jie , Xie Jianping , Gong Sitang , Zeng Huasong 

TITLE=Deficiency of GntR Family Regulator MSMEG_5174 Promotes Mycobacterium smegmatis Resistance to Aminoglycosides via Manipulating Purine Metabolism

JOURNAL=Frontiers in Microbiology

VOLUME=13

YEAR=2022

URL=https://www.frontiersin.org/journals/microbiology/articles/10.3389/fmicb.2022.919538

DOI=10.3389/fmicb.2022.919538

ISSN=1664-302X

ABSTRACT=<p>The increasing incidence of drug-resistant tuberculosis is still an emergency for global public health and a major obstacle to tuberculosis treatment. Therefore, deciphering the novel mechanisms of <italic>mycobacterial</italic> antibiotic resistance is crucial for combatting the rapid emergence of drug-resistant strains. In this study, we identified an unexpected role of <italic>Mycobacterium smegmatis</italic> GntR family transcriptional regulator MSMEG_5174 and its homologous gene <italic>Mycobacterium tuberculosis</italic> Rv1152 in aminoglycoside antibiotic resistance. Deficiency of MSMEG_5174 rendered <italic>Mycobacterium smegmatis</italic> highly resistant to aminoglycoside antibiotic treatment, and ectopic expression of Rv1152 in MSMEG_5174 mutants restored antibiotic-induced bacterial killing. We further demonstrated that MSMEG_5174 negatively regulates the expression of purine metabolism-related genes and the accumulation of purine metabolites. Moreover, overexpression of xanthine dehydrogenase MSMEG_0871 or xanthine treatment elicited a significant decrease in aminoglycoside antibiotic lethality for <italic>Mycobacterium smegmatis</italic>. Together, our findings revealed MSMEG_5174 as a metabolic regulator and hint toward unexplored crosstalk between purine metabolism and antibiotic resistance.</p>