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.

耐药性、耐受力和持久性使致病菌能够在抗生素治疗中存活，并与治疗失败和复发性感染的高风险相关。细菌抗生素持久性形成的潜在机制尚不明确。在本研究中，我们发现甘露醇酸，一种最初进化以允许细菌利用替代碳源进行生长的代谢物，作为一种信号分子，能够重新编程宿主转录组并支持持久性形成。具体而言，我们通过人类代谢组的计算机筛选发现甘露醇酸与TET2 DNA双加氧酶相互作用。进一步研究表明，由沙门氏菌产生的甘露醇酸抑制Tet2的活性，从而抑制促炎基因的表达并减弱宿主免疫防御。通过基因敲入突变、沙门氏菌的甘露醇酸产生或外源性甘露醇酸处理，Tet2的催化失活促进了小鼠和人巨噬细胞中细菌持久性形成。相反，使用维生素C刺激TET2或阻断沙门氏菌甘露醇酸的产生，可以抑制细菌抗生素耐药性并改善感染治疗结果。我们的研究揭示了Tet2在防止细菌抗生素持久性方面的先前未被认识的功能，以及甘露醇酸在重新编程宿主转录组方面的功能，这超出了能量和生物合成代谢。我们的发现还表明，刺激TET活性可能代表一种潜在的对抗细菌持久性的治疗策略。