摘要

      铜绿假单胞菌（Pseudomonas aeruginosa）是一种胞外条件致病菌，通常与易感个体的感染性并发症有关，例如那些患有HIV/AIDS和囊性纤维化等潜在疾病的个体。多株铜绿假单胞菌的耐药性是一个迅速发展的临床问题。我们之前已经证明，铜绿假单胞菌感染部位的氧水平可以强烈影响该病原体的毒力和耐药性，尽管支撑这种反应的氧感应和信号机制仍然未知。在本研究中，我们探讨了假单胞菌脯氨酰羟化酶（PPHD）在控制铜绿假单胞菌毒力和耐药性中的潜在作用。我们发现一株缺乏PPHD的铜绿假单胞菌（PAO310）表现出与细菌活力增加相关的毒性增加。此外，PPHD缺陷型铜绿假单胞菌通过增加外源转运蛋白mexEF-oprN和MexXY的表达，显示出对四环素的耐药性增强。值得注意的是，PPHD基因敲除对暴露于大气缺氧环境中的细菌的耐药性的影响是表型复制的。我们认为PPHD是一种假定的细菌氧传感器，它可以将微环境氧水平与铜绿假单胞菌的毒力和耐药性联系起来。

       Pseudomonas aeruginosa is an extracellular opportunistic bacterial pathogen commonly associated with infectious complications in susceptible individuals, such as those with underlying diseases including HIV/AIDS and cystic fibrosis. Antibiotic resistance in multiple strains of P. aeruginosa is a rapidly developing clinical problem. We have previously demonstrated that the oxygen levels at the site of P. aeruginosa infection can strongly influence virulence and antibiotic resistance in this pathogen, although the oxygen-sensing and -signaling mechanisms underpinning this response have remained unknown. In this study, we investigated the potential role of the putative oxygen sensor Pseudomonas prolyl hydroxylase (PPHD) in the control of virulence and antibiotic resistance in P. aeruginosa. We found that a P. aeruginosa strain lacking PPHD (PAO310) exhibits increased virulence associated with increased bacterial motility. Furthermore, PPHD-deficient P. aeruginosa displayed enhanced antibiotic resistance against tetracycline through increased expression of the xenobiotic transporters mexEF-oprN and MexXY. Of note, the effect of the PPHD knockout on antibiotic resistance was phenocopied in bacteria exposed to atmospheric hypoxia. We conclude that PPHD is a putative bacterial oxygen sensor that may link microenvironmental oxygen levels to virulence and antibiotic resistance in P. aeruginosa.

       https://www.jbc.org/content/295/5/1195.short