Studies on bacterial populations and new therapeutics for CF lung infections

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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. The goal of this K24 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 will allow Dr Singh to expand his translational research program, integrate fellows and junior faculty in to the program, and provide protected time so that he can mentor additional MD fellows. The project also supports research on the pathogenesis of CF infections, and on a new therapeutic approach.