Anionic polymers such as F-actin and DNA found in the airway fluid of cystic fibrosis (CF) patients and other infected sites are strong inhibitors of endogenous cationic antimicrobial peptides such as those produced at the airway epithelium. This revised proposal is focused on two types of novel non-peptide antimicrobial agents (ceragenins and cationic steroid derivatives) that preliminary studies show are equally or more potent than antibacterial peptides and that are more resistant to inactivation by F-actin and DNA. In the course of this project, we will quantify the effects of polyanionic filaments present at sites of infection on the antibacterial activities of cationic antibacterial peptides, ceragenins and cationic steroid antibiotics (CSA) in solutions of varying ionic composition that mimic the environment of the extracellular fluids in cystic fibrosis sputum and other infected settings. The polyanions to be tested include host-derived polymers such as DNA, Factin, and mucins, and the bacterial-derived polyanions lipopolysaccharide (LPS), lipoteichoic acid (L TA) and polysaccharides such as alginate. Quantifying the antibacterial activities of new non-peptide compounds will identify those that resist inhibition by polyanions. We will also determine if the mechanism used to kill bacteria by ceragenins and CSA is similar or distinct from the mechanism(s) used by antimicrobial peptides and if ceragenins and cationic steroids are effective against bacteria that resist antimicrobial peptides and conventional antibiotics. Identification of more potent antimicrobial agents that resist inactivation by polyelectrolytes would add to the range of agents capable of alleviating the pathology in cystic fibrosis and other diseases characterized by persistent infections. Penn Medicine contributes substantially to the local economy. In 2008, Penn Medicine created 37,000 jobs and $5.4 billion in regional economic activity, with the area's highly trained workforce producing more than 24,600 applications for just 840 open Penn staff research positions. The current proposal will create or retain 4 jobs.
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