Studies on bacterial populations and new therapeutics for CF lung infections

描述(由申请人提供)： 这项K24提案的目标是为辛格博士提供工资支持，使他能够将50%的时间用于指导肺部和重症护理研究员、初级教员和其他以患者为导向的慢性呼吸道感染研究。这项提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员纳入该计划。最后，该提案提供了时间和基础设施，帮助辛格博士提高他的指导技能。所描述的两个研究项目是培训内科科学家进行翻译研究的理想选择，因为它们涉及与患者面对面的互动，以及微生物学和基因组学的实验室研究。它们还将增加我们对囊性纤维化(CF)和其他慢性感染的感染发病机制的了解，并提出一种新的治疗方法。在项目1中，我们研究了一种新的抗感染方法，它使用金属镓(Ga)来扰乱细菌铁(Fe)的代谢。由于其与铁的化学相似性，在许多生物体系中，镓可以替代铁并抑制铁依赖的过程。我们的数据显示，GA杀死了条件致病菌铜绿假单胞菌(包括抗生素耐药菌株)，对生物被膜具有活性，并有效地治疗了3种不同的模式感染。我们建议进行临床前实验室研究，以进一步研究GA的活性，并对静注GA在CF患者中的药代动力学和安全性进行研究。在项目2中，我们研究了感染CF患者的铜绿假单胞菌种群的遗传多样性。在初步研究中，我们发现感染铜绿假单胞菌的菌株会进化为在宿主内产生遗传多样性的细菌种群。这一点很重要，因为多样性可以显著提高生物群落的抗逆性，以及它们利用现有资源的能力。如果这些原则适用于感染人类的细菌种群，多样性可能会增强细菌在面对宿主防御和抗生素治疗时的持续能力。我们将测量感染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加重和抗生素治疗的有效性。

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.