Morbidity and mortality in cystic fibrosis (CF) patients is ultimately attributable to persistent bacterial infections, especially involving Pseudomonas aeruginosa (Pa). Unfortunately, these infections often become resistant to available antibiotics, therefore novel therapeutic strategies are urgently needed. 

One way to fight bacterial infections is to deprive bacteria of essential nutrients (such as iron), leading to starvation and growth inhibition. Work from our and other groups has shown that the iron-mimetic metal Gallium [Ga(III)] inhibits Pa growth by limiting bacterial iron availability. Ga(III)-based anti-Pa therapies are substantiated by clinical trials showing favourable pharmacokinetics, safety, efficacy, and tolerability profiles of intravenously administered Ganite [FDA-approved Ga(NO3)3] in CF patients chronically infected by Pa. 

In this project, we have generated novel Ga(III) formulations suitable for inhalation therapy. Indeed, direct delivery to the lung represents the treatment of choice for CF lung infections, by maximizing drug concentration at the infection site and minimizing systemic side effects. The Ga(III) formulations developed within this project have shown good anti-Pa activity in vitro on a collection of 50 Pa isolates from CF patients. Notably, these new formulations displayed a protective effect in a mouse model of Pa pneumonia and the ability to enhance (up to 2-fold) Pa phagocytosis by human macrophages. Ga(III) directly delivered to the lung of mice has shown a prolonged persistence in the lung, compared to the intravenous Ga(III) administration route, and no significant signs of inflammation, supporting the feasibility and safety of the development of Ga(III)-based drugs for inhalation therapy. Overall, our findings provide interesting evidence that holds promise for future clinical application of Ga(III) inhalable formulations for the cure of Pa pneumonia in CF patients.

Pubblications

• Costabile, Gabriella et al. Boosting lung accumulation of gallium with inhalable nano-embedded microparticles for the treatment of bacterial pneumonia. International journal of pharmaceutics vol. 629 (2022): 122400
• Mitidieri, Emma et al. Intra-tracheal administration increases gallium availability in lung: implications for antibacterial chemotherapy. Pharmacological research vol. 170 (2021): 105698
• Visaggio, Daniela et al. Variable Susceptibility to Gallium Compounds of Major Cystic Fibrosis Pathogens. ACS infectious diseases vol. 8,1 (2022): 78-85