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.

抽象的 铜绿假单胞菌是人类重要的条件致病菌。这是造成的主要原因 囊性纤维化（CF）患者的发病率和死亡率以及医院获得性肺炎的主要原因。我们 提议研究一个保守的假定信号通路，我们已经证明该通路对细胞生长至关重要 以及铜绿假单胞菌对氨基糖苷类抗生素的耐药性。该通路的中心是 PA2797 和 PA2798 蛋白，人们对其知之甚少。在目标 1 中，我们建议检验以下假设：PA2797 通过发挥所谓的抗抗σ作用，增强生物体对氨基糖苷类药物的内在抵抗力 因素。特别是，我们将尝试鉴定受 PA2797 正向调节的基因以及 特别有助于氨基糖苷类耐药性。在目标 2 中，我们将确定 PA2797 和 PA2798 是否 通过调节氮相关组分之间的相互作用来控制铜绿假单胞菌的生长 磷酸转移酶系统和我们已经鉴定的小蛋白质。我们提出的研究有潜力 揭示一种新的信号转导途径如何促进重要的生长和抗生素耐药性 病原。此外，由于缺乏 PA2797 或 PA2798 的细胞生长有缺陷并且相当大。 更容易受到妥布霉素（用于治疗 CF 的一线抗生素）的杀菌作用 对于患者来说，我们提出的研究可能会对辅助疗法的开发产生影响 铜绿假单胞菌感染。