A Quinoxaline 1,4-Dioxide Activates DNA Repair Systems in Mycobacterium smegmatis: A Transcriptomic Study

TL;DR

This study shows that a quinoxaline compound activates DNA repair systems in Mycobacterium smegmatis, suggesting a new approach for tuberculosis treatment.

Contribution

The study reveals a novel mechanism of action for quinoxaline 1,4-dioxide compounds involving DNA damage and repair activation in M. smegmatis.

Findings

Exposure to LCTA-3368 upregulates genes involved in DNA repair and replication in M. smegmatis.

The compound increases reactive oxygen species concentration in a dose-dependent manner.

95 genes encoding oxidoreductase activity proteins show altered expression after treatment.

Abstract

In 2022, the World Health Organization reported that tuberculosis (TB) was the second leading cause of death globally from a single infectious agent following COVID-19. The development of new antitubercular agents with novel mechanisms of action for use in complex TB therapy is considered a key approach to combating TB. In this study, we examined the gene expression profile of M. smegmatis when exposed to a promising antituberculosis agent, quinoxaline 1,4-dioxide (QdNO) 7-chloro-2-(ethoxycarbonyl)-3-methyl-6-(piperazin-1-yl)quinoxaline-1,4-dioxide-1 (LCTA-3368). We investigated how the bacterial response changed with different minimum inhibitory concentrations (MIC) (1/4 × MIC, 1/2 × MIC, and 1 × MIC) and durations (30 min and 90 min) of treatment with the drug. Our analysis revealed significant upregulation in genes involved in DNA repair and replication processes, as well as changes in the expression of 95 genes encoding proteins with oxidoreductase activity. We additionally showed that the concentration of reactive oxygen species increases in a dose-dependent manner upon exposure of M. smegmatis to LCTA-3368. These findings support the proposed mechanism of antibacterial action of QdNOs, which is associated with the formation of free radicals leading to DNA damage.

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