# A putative Mycobacterium tuberculosis glyoxalase Rv0801 promotes bacterial fitness by alleviating methylglyoxal stress and blunts NRF2-mediated antioxidant defenses

## TL;DR

This study shows how a bacterial enzyme in tuberculosis helps the bacteria survive by reducing toxic stress and weakening the host's defenses.

## Contribution

The study identifies Rv0801 as a key glyoxalase in M. tuberculosis that suppresses host antioxidant and immune responses.

## Key findings

- Rv0801 provides MG tolerance in a mycothiol-dependent manner, essential for bacterial fitness under MG stress.
- Rv0801 suppresses the host KEAP1-NRF2 antioxidant pathway and dampens immunoprotective responses in macrophages.
- The enzyme's dual-pathway interference compromises macrophage-mediated bacterial clearance.

## Abstract

Methylglyoxal (MG), a toxic metabolic byproduct, functions as a potent antibacterial weapon deployed by macrophages. The glyoxalase system represents the primary microbial defense against MG, yet its role in Mycobacterium tuberculosis pathogenesis remains incompletely defined.

To define the function of the putative M. tuberculosis glyoxalase Rv0801 and its homolog MSMEG_5827, we used genetic engineering in Mycobacterium smegmatis MC2-155, coupled with growth and macrophage infection assays. Host mechanisms were dissected via transcriptomic and biochemical analysis of the KEAP1-NRF2 antioxidant pathway and pro-inflammatory responses.

We demonstrate that Rv0801, conferring robust MG tolerance in a mycothiol (MSH)-dependent manner, is essential for bacterial fitness under MG stress. Mechanistically, Rv0801 orchestrates a dual-pathway interference within infected macrophages: by detoxifying MG, it suppresses the host KEAP1-NRF2 antioxidant pathway and concurrently dampens immunoprotective responses. This coordinated suppression compromises macrophage-mediated bacterial clearance.

These findings establish Rv0801-mediated MG stress management as a critical virulence mechanism and highlight the bacterial glyoxalase as a promising target for tuberculosis therapy.