一种胆碱感应调节剂协调铜绿假单胞菌肺部感染的代谢适应和发病机制

IF 12.5 1区综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES

Science Advances Pub Date : 2025-10-17 DOI:10.1126/sciadv.adz1415

Yingjie Song, Xiyu Wu, Bo Song, Ziqi Zhu, Derong Dai, Qinqin Ma, Rui Bao

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引用次数: 0

摘要

铜绿假单胞菌利用宿主来源的磷脂酰胆碱（PC）建立持久性肺部感染，但代谢适应与发病机制之间的机制联系尚不清楚。在这里，我们证明胆碱（Cho）诱导的调节剂（CodR）是一种gcva型转录调节剂，在肺部感染期间作为综合毒力、抗生素耐药性和PC分解代谢的主调节剂。CodR直接结合PC降解的关键代谢物Cho，激活pchP和norA，促进外源PC/Cho的利用。全基因组分析显示，CodR靶向mexA、pslA和amrZ启动子中的保守基序，使毒力和耐受性途径同步。在小鼠肺炎模型中，codR缺失减弱了生物膜形成、III型分泌系统活性、铁载体产生和PC分解代谢，降低了细菌致病性。值得注意的是，Cho/PC预处理增强了codr依赖性抗生素耐药基因的转录激活，提高了对环丙沙星和美罗培南的耐受性。我们的研究结果阐明了一个范例，其中铜绿假单胞菌通过CodR与宿主来源的Cho合作，同时增强毒力和抗生素恢复力，暴露CodR作为一个可药物节点来破坏感染耐药性协同作用。

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A choline-sensing regulator coordinates metabolic adaptation and pathogenesis in Pseudomonas aeruginosa pulmonary infections

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A choline-sensing regulator coordinates metabolic adaptation and pathogenesis in Pseudomonas aeruginosa pulmonary infections

Pseudomonas aeruginosa exploits host-derived phosphatidylcholine (PC) to establish persistent lung infections, yet the mechanistic link between metabolic adaptation and pathogenesis remains unclear. Here, we demonstrate that choline (Cho)–induced regulator (CodR), a GcvA-type transcriptional regulator, serves as a master regulator integrating virulence, antibiotic resistance, and PC catabolism during pulmonary infection. CodR directly binds Cho, the key metabolite of PC degradation, to activate pchP and norA, facilitating exogenous PC/Cho utilization. Genome-wide profiling reveals that CodR targets conserved motifs in promoters of mexA, pslA, and amrZ, synchronizing virulence and tolerance pathways. codR deletion attenuated biofilm formation, type III secretion system activity, siderophore production, and PC catabolism, reducing bacterial pathogenicity in a murine pneumonia model. Notably, Cho/PC pretreatment potentiates CodR-dependent transcriptional activation of antibiotic resistance genes, elevating tolerance to ciprofloxacin and meropenem. Our findings elucidate a paradigm wherein P. aeruginosa co-opts host-derived Cho via CodR to simultaneously potentiate virulence and antibiotic resilience, exposing CodR as a druggable node to break infection-resistance synergies.

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来源期刊

Science Advances 综合性期刊-综合性期刊

CiteScore

21.40

自引率

1.50%

发文量

1937

审稿时长

29 weeks

期刊介绍： Science Advances, an open-access journal by AAAS, publishes impactful research in diverse scientific areas. It aims for fair, fast, and expert peer review, providing freely accessible research to readers. Led by distinguished scientists, the journal supports AAAS's mission by extending Science magazine's capacity to identify and promote significant advances. Evolving digital publishing technologies play a crucial role in advancing AAAS's global mission for science communication and benefitting humankind.