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 我们正在研究一种保守的假定信号通路，我们已经证明它对细胞生长至关重要。 以及铜绿假单胞菌对氨基糖苷类的耐药性。在这条通路的中心是PA 2797， PA 2798蛋白质，关于这一点知之甚少。在目标1中，我们提出了测试假设，PA 2797 通过发挥所谓的抗-抗-σ作用，增强生物体对氨基糖苷类的内在耐药性 因子特别是，我们将尝试鉴定受PA 2797正调控的基因， 特别有助于氨基糖苷类耐药性。在目标2中，我们将确定PA 2797和PA 2798是否 通过调节与氮相关的蛋白质组分之间的相互作用来控制铜绿假单胞菌的生长。 磷酸转移酶系统和一个小的蛋白质，我们已经确定。我们提出的研究有可能 揭示一种新型信号传导途径如何促进重要微生物的生长和抗生素耐药性 病原体此外，因为缺乏PA 2797或PA 2798的细胞对于生长是有缺陷的，并且相当大程度上不能生长。 更容易受到妥布霉素的杀菌作用，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会对开发治疗癌症的新疗法产生影响。 P.铜绿感染。