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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL067286-07
Application #
7851084
Study Section
Lung Cellular, Molecular, and Immunobiology Study Section (LCMI)
Program Officer
Banks-Schlegel, Susan P
Project Start
2001-06-01
Project End
2012-06-30
Budget Start
2010-07-01
Budget End
2012-06-30
Support Year
7
Fiscal Year
2010
Total Cost
$451,390
Indirect Cost
Name
University of Pennsylvania
Department
Physiology
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Wang, Yu-Hsiu; Bucki, Robert; Janmey, Paul A (2016) Cholesterol-Dependent Phase-Demixing in Lipid Bilayers as a Switch for the Activity of the Phosphoinositide-Binding Cytoskeletal Protein Gelsolin. Biochemistry 55:3361-9
Ku?akowska, Alina; Byfield, Fitzroy J; Zendzian-Piotrowska, Ma?gorzata et al. (2014) Increased levels of sphingosine-1-phosphate in cerebrospinal fluid of patients diagnosed with tick-borne encephalitis. J Neuroinflammation 11:193
Leszczynska, Katarzyna; Namiot, Dorota; Byfield, Fitzroy J et al. (2013) Antibacterial activity of the human host defence peptide LL-37 and selected synthetic cationic lipids against bacteria associated with oral and upper respiratory tract infections. J Antimicrob Chemother 68:610-8
Wang, Yu-Hsiu; Collins, Agnieszka; Guo, Lin et al. (2012) Divalent cation-induced cluster formation by polyphosphoinositides in model membranes. J Am Chem Soc 134:3387-95
Ellenbroek, Wouter G; Wang, Yu-Hsiu; Christian, David A et al. (2011) Divalent cation-dependent formation of electrostatic PIP2 clusters in lipid monolayers. Biophys J 101:2178-84
Kulakowska, Alina; Zajkowska, Joanna M; Ciccarelli, Nicholas J et al. (2011) Depletion of plasma gelsolin in patients with tick-borne encephalitis and Lyme neuroborreliosis. Neurodegener Dis 8:375-80
Byfield, Fitzroy J; Kowalski, Marek; Cruz, Katrina et al. (2011) Cathelicidin LL-37 increases lung epithelial cell stiffness, decreases transepithelial permeability, and prevents epithelial invasion by Pseudomonas aeruginosa. J Immunol 187:6402-9
Huisman, Elisabeth M; Wen, Qi; Wang, Yu-Hsiu et al. (2011) Gelation of semiflexible polyelectrolytes by multivalent counterions. Soft Matter 7:7257-7261
Cohen, Taylor S; Bucki, Robert; Byfield, Fitzroy J et al. (2011) Therapeutic potential of plasma gelsolin administration in a rat model of sepsis. Cytokine 54:235-8
Leszczynska, K; Namiot, A; Cruz, K et al. (2011) Potential of ceragenin CSA-13 and its mixture with pluronic F-127 as treatment of topical bacterial infections. J Appl Microbiol 110:229-38

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