Studies on bacterial populations and new therapeutics for CF lung infections

细菌种群和 CF 肺部感染新疗法的研究

• 批准号: 8720049
• 负责人: PRADEEP k SINGH
• 金额: $ 17.62万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-01 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8720049
• 关键词: Affect; Animal Model; Anti-Infective Agents; Antibiotic Resistance; Antibiotic Therapy; Antibiotics; Antimicrobial Resistance; Bacteria; Biological; Chemicals; Chronic; Clinical Research; Communities; Critical Care; Cystic Fibrosis; Data; Drug Kinetics; Environment; Equus caballus; Faculty; Funding; Gallium; Genetic Variation; Genomics; Goals; Growth; Host Defense; Human; Infection; Infusion procedures; Interdisciplinary Study; Iron; Laboratory Study; Link; Lung; Measures; Mentors; Metabolism; Metals; Microbial Biofilms; Microbiology; Modeling; Multi-Drug Resistance; Organism; Pathogenesis; Patients; Physicians; Population; Process; Pseudomonas aeruginosa; Research; Research Infrastructure; Research Personnel; Research Project Grants; Research Support; Research Training; Resistance; Resources; Scientist; Stress; System; Testing; Therapeutic; Time; Training; Translational Research; Wages; Work; combat; cystic fibrosis patients; in vivo; killings; novel; novel strategies; novel therapeutic intervention; novel therapeutics; pathogen; patient oriented research; pre-clinical; preclinical study; programs; research study; resistant strain; safety study; skills; uptake

DESCRIPTION (provided by applicant): The goal of this K24 proposal is to provide salary support for Dr Singh to allow him to spend 50% of his time mentoring pulmonary and critical care fellows, junior faculty and other trainees in patient-oriented research on chronic airway infections. This proposal also will allow Dr Singh to expand his translational research program, and integrate fellows and junior faculty in to the program. Finally, the proposal provides time and infrastructure to help Dr Singh enhance his mentoring skills. The two research projects described are ideal for training physician-scientists in translational research as they involve face-to-face interaction with patients, and laboratory studies in microbiology and genomics. They will also increase our understanding of infection pathogenesis in cystic fibrosis (CF) and other chronic infections, and advance a new therapeutic approach. In Project 1, we examine a novel anti-infective approach that uses the metal gallium (Ga) to disrupt bacterial iron (Fe) metabolism. Due to its chemical similarity to Fe, Ga can substitute for Fe in many biologic systems and inhibit Fe-dependent processes. Our data shows that Ga kills the opportunistic pathogen Pseudomonas aeruginosa (including antibiotic resistant strains), is active against biofilms, and effectively treats 3 different model infections. We propose preclinical laboratory studies to further investigate Ga's activity, and a pharmacokinetic and safety study of IV Ga in subjects with CF. In Project 2, we study genetic diversity in P. aeruginosa populations infecting CF patients. In preliminary studies, we found that infecting P. aeruginosa strains evolve to produce a genetically diverse bacterial population within the host. This is important because diversity can markedly increase the stress resistance of biological communities, and their ability to exploit available resources. If these principles apply to bacterial populations infecting humans, diversity may enhance ability of the bacteria to persist in the face of host defenses and antibiotic treatment. We will measure the genetic diversity of P. aeruginosa populations infecting CF patients, and propose experiments to understand how this diversity affects infectious exacerbations and the efficacy of antibiotic treatment.

描述（由申请人提供）： 这项K24提案的目的是为辛格博士提供薪水支持，以便他花50％的时间指导肺部和重症监护研究员，初级教师和其他学员，从事以患者为导向的慢性气道感染研究。该建议还将允许辛格​​博士扩大他的翻译研究计划，并将研究员和初级教师纳入该计划。最后，该提案提供了时间和基础设施，以帮助辛格博士提高他的指导能力。所描述的两个研究项目非常适合培训医师科学家在翻译研究中，因为它们涉及与患者的面对面相互作用以及微生物学和基因组学领域的实验室研究。它们还将增加我们对囊性纤维化（CF）和其他慢性感染中感染发病机理的理解，并提高一种新的治疗方法。在项目1中，我们检查了一种新型的抗感染方法，该方法使用金属着甘油（GA）破坏细菌铁（Fe）代谢。由于其与FE的化学相似性，GA可以在许多生物系统中代替FE，并抑制FE依赖性过程。我们的数据表明，GA杀死了铜绿假单胞菌（包括抗生素抗菌菌株）的机会性病原体，对生物膜有效，并有效地治疗了3种不同的模型感染。我们提出了临床前实验室研究，以进一步研究GA的活性，以及​​对CF受试者的IV GA的药代动力学和安全性研究。在项目2中，我们研究了感染CF患者的铜绿假单胞菌种群中的遗传多样性。在初步研究中，我们发现感染铜绿假单胞菌菌株会在宿主内部产生遗传多样的细菌种群。这很重要，因为多样性可以显着提高生物社区的压力抵抗力，以及它们利用可用资源的能力。如果这些原理适用于感染人类的​​细菌种群，那么在宿主防御和抗生素治疗方面，多样性可能会增强细菌持续存在的能力。我们将衡量感染CF患者的铜绿假单胞菌种群的遗传多样性，并提出实验以了解这种多样性如何影响感染性加重和抗生素治疗的疗效。