Abstract：
Polymyxins are often the only effective antibiotics against the \"Critical\" pathogen Acinetobacter baumannii. Worryingly, highly polymyxin-resistant A. baumannii displaying dependence on polymyxins has emerged in the clinic, leading to diagnosis and treatment failures. Here, we report that arginine metabolism is essential for polymyxin-dependent A. baumannii. Specifically, the arginine degradation pathway was significantly altered in polymyxin-dependent strains compared to wild-type strains, with critical metabolites (e.g., L-arginine and L-glutamate) severely depleted and expression of the astABCDE operon significantly increased. Supplementation of arginine increased bacterial metabolic activity and suppressed polymyxin dependence. Deletion of astA, the first gene in the arginine degradation pathway, decreased phosphatidylglycerol and increased phosphatidylethanolamine levels in the outer membrane, thereby reducing the interaction with polymyxins. This study elucidates the molecular mechanism by which arginine metabolism impacts polymyxin dependence in A. baumannii, underscoring its critical role in improving diagnosis and treatment of life-threatening infections caused by \"undetectable\" polymyxin-dependent A. baumannii.
摘要：
多粘菌素通常是针对“关键”病原体鲍曼不动杆菌的唯一有效抗生素。令人担忧的是,高度多粘菌素抗性的鲍曼不动杆菌显示对多粘菌素的依赖已经出现在临床上，导致诊断和治疗失败。这里,我们报告说，精氨酸代谢对多粘菌素依赖性鲍曼不动杆菌至关重要。具体来说,与野生型菌株相比，多粘菌素依赖性菌株的精氨酸降解途径显着改变，与关键代谢物(例如，L-精氨酸和L-谷氨酸）严重耗尽，astABCDE操纵子的表达显着增加。补充精氨酸可增加细菌代谢活性并抑制多粘菌素依赖。删除astA,精氨酸降解途径中的第一个基因，减少磷脂酰甘油和增加磷脂酰乙醇胺水平在外膜，从而减少与多粘菌素的相互作用。本研究阐明了精氨酸代谢影响鲍曼不动杆菌多粘菌素依赖的分子机制。强调其在改善由“无法检测”的多粘菌素依赖性鲍曼不动杆菌引起的危及生命的感染的诊断和治疗中的关键作用。
