Cystic Fibrosis (CF) is an autosomal recessive disorder, which leads to the abnormal composition and physical properties of airway secretions in CF patients. Additionally, the lungs of CF patients are particularly susceptible to chronic bacterial infections with >80% of CF patients becoming chronically infected by 18 years of life with mucoid forms of Pseudomonas aeruginosa that over-produce the surface polysaccharide alginate. The long term goal of this project (which is outside the scope of this application) is to investigate the use of gallium nitrate as an anti-infective to treat chronic P. aeruginosa lung infections in CF patients. The major hypothesis to be tested is whether gallium nitrate can be used to reduce P. aeruginosa lung infections and result in improvement in lung function. One key observation of P. aeruginosa infections in CF is that the patients ultimately succumb to bacterial infections despite being on a regiment of antibiotics. It is believed that bacterial resistance is a major reason for treatment failure, allowing the organism to escape elimination by acquired host immune defenses and underlies the progressive decline in lung function. Gallium nitrate was found to be bactericidal in vitro against both Gram- and Gram+ bacteria, particularly against bacteria that are found to chronically colonize the lungs of CF patients, such as P. aeruginosa, Burkholderia cepacia and methycillin-resistant Staphylococcus aureus (MRSA). Galllium was protective against mucoid strains of P. aeruginosa isolated from patients with nosocomial infections. Preliminary data indicate that gallium is effective against bacterial resistant Pa strains as well as recent strains isolated from fresh sputum. In this application, we propose further preclinical development of gallium nitrate and testing the protective activities against acute P. aeruginosa pulmonary infection in wild- type (WT) mice. We will first develop an optimal aerosol formulation using a spray drying process, characterize the aerosol properties, and confirm that lead formulations can be efficiently delivered from conventional, commercially available inhalers. We will perform preclinical testing of optimized aerosol formulation in a mouse inhalation model to assess its residence time and biodistribution, followed by determination of the minimal protective dose in a bacterial challenge study.
The studies proposed in this application are designed to further development of a new anti-infective candidate gallium nitrate to treat chronic Pseudomonas aeruginosa lung infections of CF patients. At present, 80-95% of CF patients ultimately succumb to respiratory failure due to chronic P. aeruginosa infection and airway inflammation.
| Kelson, Andrew B; Carnevali, Maia; Truong-Le, Vu (2013) Gallium-based anti-infectives: targeting microbial iron-uptake mechanisms. Curr Opin Pharmacol 13:707-16 |
