复旦大学上海医学院叶丹团队在研究中取得进展。他们的研究发现病原体衍生的乙醛酸盐抑制Tet2 DNA双加氧酶，促进细菌持久性形成。这一研究成果发表在2025年3月3日出版的国际学术期刊《细胞—代谢》上。

该课题组人员发现乙醛酸盐是一种最初为替代碳利用而进化的代谢物，它作为一种信号分子，可以重编程宿主转录组并促进持久性形成。乙醛酸酯抑制DNA双加氧酶TET2，抑制促炎基因表达，减弱宿主免疫防御。值得注意的是，用维生素C刺激TET2活性或阻断沙门氏菌产生乙醛酸盐可降低细菌对抗生素的耐药性，提高感染治疗效果。

除了代谢作用外，乙醛酸盐还作为宿主-病原体相互作用的调节剂，而TET2在防止细菌持久性方面起着关键作用。他们的研究结果表明，靶向乙醛酸盐的产生或增强TET2活性提供了有希望的治疗策略，以对抗细菌的持久性和提高抗生素治疗的疗效。

据了解，病原菌的持续存在使抗生素治疗期间存活，导致治疗失败和复发性感染，但其潜在机制尚不清楚。

附：英文原文

Title: Pathogen-derived glyoxylate inhibits Tet2 DNA dioxygenase to facilitate bacterial persister formation

Author: Zhou-Li Cheng, Shuyuan Zhang, Zhenning Wang, Aixia Song, Chao Gao, Jun-Bin Song, Pu Wang, Lei Zhang, Yue Zhou, Wenyan Shan, Chen Zhang, Jinye Zhang, Yiping Sun, Yanhui Xu, Fei Lan, Ming Zhong, Liang-Dong Lyu, Guanghua Huang, Fei Xavier Chen, Gang Li, Zixin Wang, Faying Chen, Jianhuang Xue, Jiejun Shi, Yujun Liu, Zihao Lin, Duojiao Wu, Jim Na, Lei-Lei Chen, Kun-Liang Guan, Yue Xiong, Dan Ye

Issue&Volume: 2025-03-03

Abstract: Pathogenic bacterial persistence enables survival during antibiotic treatment, leading to treatment failure and recurrent infections, yet its underlying mechanisms remain unclear. Here, we reveal that glyoxylate, a metabolite originally evolved for alternative carbon utilization, functions as a signaling molecule to reprogram the host transcriptome and promote persister formation. Glyoxylate inhibits the DNA dioxygenase TET2, suppressing pro-inflammatory gene expression and attenuating host immune defense. Notably, stimulating TET2 activity with vitamin C or blocking glyoxylate production by Salmonella reduces bacterial antibiotic resistance and improves infection treatment outcomes. Beyond its metabolic role, glyoxylate emerges as a regulator of host-pathogen interactions, while TET2 plays a critical role in preventing bacterial persistence. Our findings suggest that targeting glyoxylate production or enhancing TET2 activity offers promising therapeutic strategies to combat bacterial persistence and enhance the efficacy of antibiotic treatments.

DOI: 10.1016/j.cmet.2025.01.019

Source: https://www.cell.com/cell-metabolism/abstract/S1550-4131(25)00020-8