MUC1 decoy peptides for treatment and prevention of bacterial infections
Pseudomonas aeruginosa flagellin protein recruits the mammalian host sialidase enzyme neuraminidase-1 (NEU1) to remove sialic acid residues from the extracellular domain of the mammalian cell-surface protein MUC1 (MUC1-ED), thereby exposing a cryptic binding site on the MUC1-ED protein backbone for flagellin binding. NEU1-driven MUC1-ED desialylation rapidly increases P. aeruginosa adhesion to the airway epithelium. MUC1-ED desialylation also increases MUC1-ED cleavage and shedding from the cell surface, where desialylated, shed MUC1-ED competitively blocks P. aeruginosa adhesion to cell-associated MUC1-ED. Presented herein are data showing that exogenously-administered, deglycosylated MUC1-ED peptides reduced adhesion of P. aeruginosa to airway epithelial cells. Also presented are data showing that administration of P. aeruginosa to mice in combination with deglycosylated MUC1-ED decreased P. aeruginosa recovered from the lungs at 48 hr and 72 hr post-infection. Such findings are extended to the methods of treatment and prevention of bacterial infections defined herein.
1. A method of treating or preventing a pulmonary infection caused by Pseudomonas aeruginosa in a subject, comprising administering to the subject a therapeutically effective amount of an ectodomain MUC1 decoy peptide comprising the amino acid sequence set forth in SEQ ID NO:3.
2. The method of claim 1 , wherein the pulmonary infection is treated.
3. The method of claim 1 , wherein the pulmonary infection is an infection of the lungs of a subject with cystic fibrosis or a ventilator-associated pneumonia.
4. The method of claim 1 , wherein the ectodomain MUC1 decoy peptide is formulated in a pharmaceutical formulation comprising the peptide and a pharmaceutically acceptable carrier or diluent.
5. The method of claim 1 further comprising administering a therapeutically effective amount of one or more antibiotics to the subject.
6. The method of claim 5 , wherein the one or more antibiotics are formulated in a pharmaceutical formulation comprising the antibiotic and a pharmaceutically acceptable carrier or diluent.
7. The method of claim 5 wherein the ectodomain MUC1 decoy peptide comprises the amino acid sequence set forth in SEQ ID NO:3 the antibiotic is cefepime.
8. The method of claim 5 wherein the ectodomain MUC1 decoy peptide and the one or more antibiotics are administered to the subject via separate administrations.
9. The method of claim 1 , wherein the administering comprises administering by inhalation.