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RND 型多重耐药外排泵的缺失会触发铜绿假单胞菌的铁饥饿和脂 A 修饰。

Loss of RND-Type Multidrug Efflux Pumps Triggers Iron Starvation and Lipid A Modifications in Pseudomonas aeruginosa.

机构信息

University of Oklahomagrid.266900.b, Department of Chemistry and Biochemistry, Norman, Oklahoma, USA.

University of Maryland, Baltimore, Department of Microbial Pathogenesis, Baltimore, Maryland, USA.

出版信息

Antimicrob Agents Chemother. 2021 Sep 17;65(10):e0059221. doi: 10.1128/AAC.00592-21. Epub 2021 Jul 12.

Abstract

Transporters belonging to the esistance-odulation-ivision (RND) superfamily of proteins are invariably present in the genomes of Gram-negative bacteria and are largely responsible for the intrinsic antibiotic resistance of these organisms. The numbers of genes encoding RND transporters per genome vary from 1 to 16 and correlate with the environmental versatilities of bacterial species. Pseudomonas aeruginosa strain PAO1, a ubiquitous nosocomial pathogen, possesses 12 RND pumps, which are implicated in the development of clinical multidrug resistance and known to contribute to virulence, quorum sensing, and many other physiological functions. In this study, we analyzed how P. aeruginosa's physiology adapts to a lack of RND-mediated efflux activities. A combination of transcriptomics, metabolomics, genetic, and analytical approaches showed that the P. aeruginosa PΔ6 strain, lacking the six best-characterized RND pumps, activates a specific adaptation response that involves significant changes in the abundance and activities of several transport system, quorum sensing, iron acquisition, and lipid A modification pathways. Our results demonstrate that these cells accumulate large quantities of Pseudomonas quinolone signals (PQS), which triggers iron starvation and activation of siderophore biosynthesis and acquisition pathways. The accumulation of iron in turn activates lipid A modification and membrane protection pathways. A transcriptionally regulated RND pump, MuxABC-OpmB, contributes to these transformations by controlling the concentration of coumarins. Our results suggest that these changes reduce the permeability barrier of the outer membrane and are needed to protect the cell envelope of efflux-deficient P. aeruginosa.

摘要

属于耐药-调制-分隔(RND)蛋白超家族的转运蛋白在革兰氏阴性菌的基因组中普遍存在,并且在很大程度上导致了这些生物体的固有抗生素耐药性。每个基因组编码 RND 转运蛋白的基因数量从 1 到 16 不等,并且与细菌物种的环境多功能性相关。铜绿假单胞菌 PAO1 菌株是一种普遍存在的医院病原体,拥有 12 个 RND 泵,这些泵与临床多药耐药性的发展有关,并且已知与毒力、群体感应和许多其他生理功能有关。在这项研究中,我们分析了铜绿假单胞菌的生理如何适应缺乏 RND 介导的外排活性。转录组学、代谢组学、遗传和分析方法的组合表明,缺乏六个最佳表征的 RND 泵的 P. aeruginosa PΔ6 菌株激活了一种特定的适应反应,涉及到几种转运系统、群体感应、铁获取和脂 A 修饰途径的丰度和活性的显著变化。我们的结果表明,这些细胞积累了大量的铜绿假单胞菌喹诺酮信号(PQS),这会引发铁饥饿并激活铁载体生物合成和获取途径。铁的积累反过来又激活了脂 A 修饰和膜保护途径。一个转录调节的 RND 泵 MuxABC-OpmB 通过控制香豆素的浓度对这些转化做出贡献。我们的结果表明,这些变化降低了外膜的通透性屏障,并且对于缺乏外排的铜绿假单胞菌的细胞包膜保护是必需的。

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