Kou Tian-Shun, Shang Yan-Yan, Zhang Qi-Chao, Tian Si-Qi, Li Juan, Yang Li-Na, Min Ling, Peng Bo
Guangzhou Institute of Cancer Research, The Affiliated Cancer Hospital, Guangzhou Medical University, Guangzhou, China.
State Key Laboratory of Bio-Control, Guangdong Key Laboratory of Pharmaceutical Functional Genes, School of Life Sciences, Southern Marine Science and Engineering Guangdong Laboratory (Zhuhai), Sun Yat-Sen University, Guangzhou, China.
Virulence. 2025 Dec;16(1):2545558. doi: 10.1080/21505594.2025.2545558. Epub 2025 Aug 11.
, a common pathogen responsible for bloodstream infections, can evade clearance by the complement-dependent killing in serum, known as serum resistance. However, strategy in managing serum resistance is still lacking. In this study, we employed metabolomics to identify the metabolic features of . We found that the pyruvate/TCA cycle and alanine, aspartate, and glutamate metabolic pathways were significantly downregulated. Proline, identified as a key biomarker, effectively increased the serum sensitivity to multiple clinical isolates and restored the bactericidal activity of complement. The synergistic effect of proline was validated in a murine infection model. Furthermore, we demonstrated that proline activates the pyruvate/TCA cycle, increases proton motive force, and enhances complement proteins binding to bacterial surface, forming membrane attack complex to kill serum-resistant . Our findings provide new insights for the development of metabolism-based approach to manage serum resistance and offer potential targets and strategies for host immunity-based anti-infection therapies.
作为血流感染的常见病原体，能够逃避血清中补体依赖性杀伤作用，即血清抗性。然而，目前仍缺乏应对血清抗性的策略。在本研究中，我们运用代谢组学来鉴定的代谢特征。我们发现丙酮酸/三羧酸循环以及丙氨酸、天冬氨酸和谷氨酸代谢途径显著下调。脯氨酸被鉴定为关键生物标志物，它能有效提高血清对多种临床分离株的敏感性，并恢复补体的杀菌活性。脯氨酸的协同效应在小鼠感染模型中得到验证。此外，我们证明脯氨酸激活丙酮酸/三羧酸循环，增加质子动力，并增强补体蛋白与细菌表面的结合，形成膜攻击复合物以杀死血清抗性的。我们的研究结果为开发基于代谢的方法来应对血清抗性提供了新见解，并为基于宿主免疫的抗感染治疗提供了潜在靶点和策略。
