Pseudomonas and Aspergillus cause life threatening lung infections. Antibiotics to treat these infections are not always effective, and new treatment approaches are urgently needed. We propose to prevent Pseudomonas or Aspergillus binding to mucin glycans based on disruption of the protein carbohydrate interactions frequently used in mechanisms of host infection. We .will use glycomimetic decoys to disrupt fucose-based interactions with an emphasis on inhibiting fucophilic PA-IIL lectin from Pseudomonas and AFL lectin from Aspergillus. In this way we will prevent microbial adhesion to mucins and mucin-covered cell surfaces, and we will inhibit the mucin cross-linking caused by these multimeric lectins. We have a multidisciplinary group that includes Drs Roy and Oscarson, two glycochemists with long experience in glycomimetic synthesis.
AIM 1 will screen multivalent fucose structures for potency as inhibitors of PA-llL and AFL binding to ainway mucins. For inhibition of PA-llL, we will test candidate fucoside glycodendrimers already synthesized by Dr Roy's laboratory. For inhibition of AFL, we will test multivalent fucose inhibitors newly synthesized by the Oscarson laboratory. Inhibition will be tested in plate-based assays that use labeled lectins and native ain/vay mucins purified from healthy ainway mucus. We will also use labeled lectins and cultured airway epithelial cells in a FACS-based assay to test the efficacy of glycomimetics as inhibitors of lectin binding to mucins on epithelial cell surfaces.
AIM 2 will screen multivalent fucose structures for efficacy as mucolytic drugs in cystic fibrosis (CF). Sputum in CF is frequently infected with Pseudomonas aeruginosa and Aspergillus fumigatus, and these organisms contribute to the abnormal viscoelastic properties of the airway mucus that contributes to poor mucus clearance and to chronic airway infection. We will test the best inhibitors of PA-llL and AFL identified in Aim 1 for efficacy as mucolytics in Aim 2, using an ex vivo assay in which we will measure the elastic properties of CF sputum before and after addition of glycomimetics. Rheology will provide a measure of mucin cross-linking in the mucus samples so that we can determine the mucolytic effects of candidate carbohydrates.
The research proposed here aims to develop new treatment approaches for lung infections caused by pseudomonas and aspergillus, two important causes of pneumonia. Our strategy will involve the use of sugar-like compounds that will interfere with how these infectious organisms bind to the lining ofthe lung. If successful in the tests we propose in our grant, these compounds could be used as human treatments within a relativelv short time frame.
| Kerr, Sheena C; Fischer, Gregory J; Sinha, Meenal et al. (2016) FleA Expression in Aspergillus fumigatus Is Recognized by Fucosylated Structures on Mucins and Macrophages to Prevent Lung Infection. PLoS Pathog 12:e1005555 |
| Lachowicz-Scroggins, Marrah E; Yuan, Shaopeng; Kerr, Sheena C et al. (2016) Abnormalities in MUC5AC and MUC5B Protein in Airway Mucus in Asthma. Am J Respir Crit Care Med 194:1296-1299 |
| Yuan, Shaopeng; Hollinger, Martin; Lachowicz-Scroggins, Marrah E et al. (2015) Oxidation increases mucin polymer cross-links to stiffen airway mucus gels. Sci Transl Med 7:276ra27 |
| Fahy, John V; Dickey, Burton F (2010) Airway mucus function and dysfunction. N Engl J Med 363:2233-47 |
