A signaling pathway governing growth and antibiotic sensitivity in Pseudomonas aeruginosa

控制铜绿假单胞菌生长和抗生素敏感性的信号通路

• 批准号: 9807023
• 负责人: SIMON L DOVE
• 金额: $ 26.55万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-06-01 至 2021-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9807023
• 关键词: Aminoglycoside Antibiotics; Aminoglycoside resistance; Aminoglycosides; Anti-Bacterial Agents; Antibiotic Resistance; Antibiotics; Cells; Chronic; Defect; Development; Exhibits; Genes; Growth; Lung; Lung infections; Molecular; Morbidity - disease rate; Nitrogen; Nosocomial pneumonia; Organism; Pathway interactions; Patients; Phosphotransferases; Protein phosphatase; Proteins; Pseudomonas aeruginosa; Pseudomonas aeruginosa infection; Resistance; Sigma Factor; Signal Pathway; Signal Transduction Pathway; System; Testing; Tobramycin; Work; bactericide; base; cell growth; clinically relevant; cystic fibrosis patients; human pathogen; mortality; novel; pathogen; ventilator-associated pneumonia

Abstract Pseudomonas aeruginosa is an important opportunistic pathogen of humans. It is the principal cause of morbidity and mortality in Cystic Fibrosis (CF) patients and a major cause of hospital-acquired pneumonia. We are proposing to study a conserved putative signaling pathway that we have shown is critical for cell growth and for resistance to aminoglycosides in P. aeruginosa. At the center of this pathway are the PA2797 and PA2798 proteins, about which relatively little is known. In Aim 1 we propose to test the hypothesis that PA2797 enhances the intrinsic resistance of the organism to aminoglycosides by functioning as a so-called anti-anti-σ factor. In particular, we will attempt to identify genes that are positively regulated by PA2797 and that specifically contribute to aminoglycoside resistance. In Aim 2 we will determine whether PA2797 and PA2798 govern the growth of P. aeruginosa by modulating the interaction between a component of the nitrogen-related phosphotransferase system and a small protein we have identified. Our proposed studies have the potential to reveal how a novel signal transduction pathway promotes the growth and antibiotic resistance of an important pathogen. Moreover, because cells lacking PA2797 or PA2798 are defective for growth and are considerably more susceptible to the bactericidal effects of tobramycin, the frontline antibiotic used in the treatment of CF patients, our proposed studies could have implications for the development of adjunctive therapies for treating P. aeruginosa infections.

摘要 铜绿假单胞菌是人类重要的条件致病菌。这是导致 囊性纤维化(CF)患者的发病率和死亡率是医院获得性肺炎的主要原因。我们 正在提议研究我们已经证明对细胞生长至关重要的保守的假定信号通路 铜绿假单胞菌对氨基糖苷类药物的耐药性。这条路径的中心是PA2797和 PA2798蛋白质，人们对其知之甚少。在目标1中，我们建议检验PA2797的假设 通过发挥所谓的抗σ抗体的作用，增强机体对氨基糖苷类药物的内在抵抗力 因素。特别是，我们将尝试识别受PA2797正向调控的基因，以及 特别是对氨基糖苷类耐药有贡献。在目标2中，我们将确定PA2797和PA2798 通过调节与氮相关的成分之间的相互作用来控制铜绿假单胞菌的生长 磷酸转移酶系统和一个我们已经鉴定的小蛋白。我们提议的研究有可能 揭示一种新的信号转导途径如何促进重要的 病原体。此外，因为缺乏PA2797或PA2798的细胞生长有缺陷，而且相当大 更易受妥布霉素的杀菌作用的影响，妥布霉素是治疗CF的一线抗生素 患者，我们提出的研究可能对开发辅助治疗治疗有意义。 铜绿假单胞菌感染。