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

Haiqi Chen¹Qi'ao Zhang¹Xinyi He¹Abulimiti Abudukadier¹Yun Qi²Qun Sun^3*Peibo Li^4*Jianping Xie^1*

• ¹Southwest University, Chongqing, China
• ²Xi'an Chest Hospital, Xi'an, China
• ³Sichuan University, Chengdu, China
• ⁴Chongqing Public Health Medical Center, Chongqing, China

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. Here we demonstrate that a putative M. tuberculosis glyoxalase 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. Our findings establish Rv0801-mediated MG stress management as a critical virulence mechanism and highlight the bacterial glyoxalase as a promising target for tuberculosis therapy.