Glyoxylate-Tet2

Resistance, tolerance and persistence enable pathogenic bacteria to survive antibiotic treatment and are associated with an elevated risk of treatment failure and relapsing infections. The mechanism underlying bacterial antibiotic persister formation is not well understood. Here, we show that glyoxylate, a metabolite originally evolved to allow bacteria to utilize alternative carbon sources for growth, serves as a signaling molecule to reprogram host transcriptome and support persister formation. Specifically, we discovered glyoxylate interacting with TET2 DNA dioxygenase through an in-silico screen of human metabolome. We further show that Salmonella-produced glyoxylate inhibits the activity of Tet2 to suppress the expression of pro-inflammatory genes and attenuate host immune defense. Catalytic inactivation of Tet2, by genetic knock-in mutation, glyoxylate production by Salmonella, or exogenous glyoxylate treatment, facilitates bacterial persister formation in both murine and human macrophages. Conversely, stimulating TET2 with vitamin C or blocking Salmonella production of glyoxylate suppresses bacterial antibiotic resistance and improves the infection treatment outcomes. Our study uncovers a previously unrecognized function of Tet2 in preventing bacterial antibiotic persistence and the function of glyoxylate in reprograming host transcriptome beyond energetic and biosynthetic metabolism. Our findings also suggest that stimulating TET activity represents a potential therapeutic strategy to combat bacterial persistence.