Chronic respiratory disease, hallmarked by recalcitrant airway infection involving mixed bacterial flora combined with persistent neutrophilic inflammation, is the 3rd leading cause of death in the US and remains a significant treatment challenge. This application proposes the development of novel, inhaled therapeutic agents to treat the underlying infection and inflammation in chronic lung diseases. The compound series has a novel bactericidal mechanism without evidence of resistance and dual anti-inflammatory activity (inhibits neutrophil migration and cytokine release). The antibiotic activity targets most relevant pathogens in bronchiectasis and potentiates the activity of aminoglycosides (e.g. tobramycin) for Gram-positive organisms and polymyxins (e.g. Colistin) for Gram-negatives. Potentiation with Tobramycin improves activity against Gram-positive persister bacteria and biofilms. Preliminary in vivo safety studies demonstrated pulmonary tolerability after 12 days of administration (at effective doses), as well as, with IV dosing. This program has the potential to address a significant unmet need in bronchiectasis and provide new treatment options against the growing threat of antibiotic resistance.
Public Health Relevance Statement: NARRATIVE Chronic respiratory disease, which is characterized by bacterial infections and persistent inflammation, is the 3rd leading cause of death in the US and remains a significant treatment challenge. This application describes the identification and characterization of a compound which appears well suited to address this growing unmet medical need based on its ability to treat bacterial infections and inflammation in the lung.
Project Terms: Address; Airway Disease; airway epithelium; airway obstruction; Aminoglycoside resistance; Aminoglycosides; analog; Anti-Inflammatory Agents; Antibiotic Resistance; antibiotic tolerance; Antibiotics; Antiinflammatory Effect; Antimicrobial Effect; aqueous; Aztreonam; Bacteria; Bacterial Infections; bacterial resistance; bactericide; base; Binding; Binding Proteins; Bronchi; Bronchiectasis; Cause of Death; Chemistry; Chemosensitization; Chronic; Chronic lung disease; Chronic Obstructive Airway Disease; Ciprofloxacin; Clinical; Clinical Trials; Colistin; Constitutional Symptom; Coughing; Cystic Fibrosis; cytokine; cytotoxicity; design; Development; Disease; DNA Sequence Alteration; Dose; Drug Delivery Systems; effective therapy; Elastases; Environment; Epithelial Cells; experience; Failure; Frequencies; functional group; Goals; Human; Immunity; improved; in vivo; Incidence; Infection; Inflammation; Inflammation Mediators; Inhalation; lipophilicity; Lung; Lung diseases; Lung infections; Lung Inflammation; Macrolide-resistance; Macrolides; Medical; Microbial Biofilms; migration; Mucins; Mucous body substance; mucus clearance; neutrophil; Neutrophil Infiltration; novel; novel therapeutics; Nutrient; Oral; Organism; pathogen; Patients; Pharmaceutical Preparations; physical property; Physiological; Physiology; Placebos; preservation; Prevalence; prevent; Prevention; Prevention therapy; programs; Property; Recurrence; Resistance; respiratory; safety study; screening; Secondary to; Series; side effect; small molecule; Solubility; Sputum; Surface; Testing; Therapeutic; Therapeutic Agents; therapeutic target; Thick; Time; Tobramycin; Triage; Water
