Nebulized Nitrite as a Novel Antimicrobial Therapy in Cystic Fibrosis

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 DESCRIPTION (provided by applicant): This application for a Mentored Patient-Oriented Research Career Development Award is being submitted by Anna Zemke, MD PhD and entitled "Nebulized Nitrite as a Novel Antimicrobial Therapy in Cystic Fibrosis." Dr. Zemke is a pulmonologist at the University of Pittsburgh and requires additional training in human subjects research to continue her professional development toward the long-term goal of conducting translational pulmonary research, with a focus on chronic bacterial infections. The short-term training goals of this proposal are to: (1) Gain an in-depth understanding of conducting pulmonary translational studies, (2) Become an expert in the biology of pulmonary bacterial infections, and (3) Become proficient at techniques used to study bacterial physiology. Integral to the training plan is the Certificate in Clinical Research Program, which includes needed statistical, ethical, and regulatory training. This work will be conducted within the Division of Pulmonary, Allergy, and Critical Care at the University of Pittsburgh, which has a strong history of training physician- scientists and a superb infrastructure for both training Dr. Zemke and conducting the proposed translational research. The central objective of this research proposal is to develop nebulized sodium nitrite as an antimicrobial agent in cystic fibrosis (CF). Cystic fibrosis is the most common lethal disease among Caucasian Americans and is marked by progressive respiratory failure and airway infections. Pseudomonas aeruginosa infects up to 80% of adults with CF, and grows in highly antibiotic resistant biofilms within the lung. Triggerin bacteria to disperse from biofilms may allow for improved clearance by the host and improved antibiotic efficacy. Sodium nitrite (AIR001) is an agent that combines antimicrobial activity, through the suppression of bacterial respiration, with the ability to disperse established biofilms When AIR001 is combined with colistimethate, it has additional activity against P. aeruginosa biofilms. AIR001 has not been tested in the CF population, but it has excellent safety data in pulmonary hypertension patients. The first research aim consists of proof-of-concept studies for developing nebulized nitrite and colistimethate combinations for treating P. aeruginosa airway infections in adults with CF. This aim tests the hypothesis that nebulization of nitrite and colistimethate is safe in subjects with CF and collects proof-of-concept efficacy data. The second aim will test the hypothesis that nitrite disperses biofilms in a nutritionally complex environment and then determine the mechanism of nitrite-induced biofilm dispersal. The combination of (1) formal human subjects research training;(2) hands-on, innovative research experience that includes both early phase safety protocols and further basic science; (3) an experienced, diverse mentorship team; and (4) the strong institutional environment of the Pulmonary, Allergy, and Critical Care Division at the University of Pittsburgh will equip Dr. Zemke for a career in translational pulmonary research.