Gallium as an antibacterial agent in cystic fibrosis: animal studies for the delivery of inhalable formulations to the clinic

Morbidity and mortality in cystic fibrosis (CF) patients is primarily attributable to persistent pulmonary infection caused by Pseudomonas aeruginosa. The emergence of antibiotic resistance in P. aeruginosa has become a worrisome problem that urgently demands new antimicrobials and new drug targets. Over the past 12 years, work from our and other groups have shown that Gallium (Ga3+) inhibits P. aeruginosa growth, acting as an iron mimetic. The perspective of bringing Ga(III)-based anti-P. aeruginosatherapies to the clinic has recentlybeen substantiated by a pilot trial showing favourable pharmacokinetics, safety and tolerability profiles of intravenously (i.v.) administered Ganite® [FDA-approved Ga(NO3)3] in CF patients chronically infected by P. aeruginosa. Hypothesis and objectives Over the last years, drug delivery to the respiratory tract has become of choice for the treatment of CF lung infections. Confining the antimicrobial agent to the airways maximizes drug concentration at the site of infection thereby improving the therapeutic efficacy, and minimizing systemic side effects. The main objective of the present project is to provide evidence of in vivo antibacterial activity of novel inhalable Ga(III) formulations, in order to gain essential pre-clinical insights for the delivery of improved/novel Ga(III)-based drugs to the clinic. The experimental activity is organized in four tasks that will be accomplished in 2 years, as follow: i) the anti-P. aeruginosa activity of selected Ga(III) formulations on a representative collection ofP.aeruginosaCF isolates; ii) the property of Ga(III) formulations to reduce inflammation in human white blood cells; iii) the toxicity and bio-distribution of Ga(III) formulations after administration (intratracheal or nasal instillation) in mice; iv) the protective efficacy of Ga(III) formulations after single intratracheal administration or multiple intranasal instillations of Ga(III) in mice bearing P. aeruginosainfections. We expect to identify a suitable Ga(III) formulation and appropriate dosing regimens for successful treatment of P. aeruginosa lung infection in mice. Our preclinical study will foster future clinical application of Ga(III) inhalable formulations for the treatment of P. aeruginosachronic lung infection in individuals with CF.