UC San Diego

Cystic Fibrosis (CF) is an autosomal recessive disorder caused by mutations to the Cystic Fibrosis Transmembrane-conductance Regulator (CFTR) gene, that leads to the buildup of thickened mucus in the lungs that are chronically infected by bacteria (often antibiotic resistant) and fungi. These chronic infections periodically flare in acute events called pulmonary exacerbations which leads to scarring of the lung and permanent decline in pulmonary function. This work presents a model of CF lung disease that incorporates the taxonomic diversity observed in the CF lung into ecological guilds based on their role in the CF sputum environment, resulting in the proposal of four functional groups called the Brewers (fermenting microbes), Drunkers (biofilm building consumers of fermentation products), Putrifiers (anaerobic biofilm dwelling bacteria) and Nihilists (lone wolf pathogens of the lung). Another model of the CF lung microbiome, found in this dissertation, predicts the succession of bacteria in CF sputum based on the concentration of succinate found in the sputum environment, which is known to be substantially higher than sputum from people without CF. The second model is based on the differential succinate flux values predicted by GEnome scale metabolic Models (GEMs) for the 29 most prevalent bacterial species in the CF lung, and observations of in vitro growth data of a mock community of four CF isolated strains of bacteria. The results of which support the existence of two distinct consortia of bacteria in the CF lung, consortium 1 made up of typical CF pathogens which can metabolize succinate and consortium 2 which contains bacteria associated with the human oral cavity that do not metabolize succinate and are likely inhibited by succinate at high concentrations. Lastly, with the aim to address the issue of treating antibiotic resistant bacterial infections in patients with CF or otherwise, this dissertation presents two engineered tailocins MobyWanKenobi and John Henry, that bind to and kill CF isolated strains of Stenotrophomonas maltophilia and both Staphylococcus aureus and Serratia odorifera respectively.