The activity of a Ga(III) catecholate complex against Aspergillus fumigatus in conditions mimicking cystic fibrosis lung and inhaled formulations for its pulmonary administration

Azole-resistant Aspergillus fumigatus (A. fumigatus) is an emerging worldwide pathogen. Pulmonary aspergillosis primarily affects severely immunocompromised patients and is also a particularly critical condition for cystic fibrosis (CF) patients. A recently designed gallium polypyridyl catecholate complex, GaS1, has previously demonstrated in vitro and in vivo antimicrobial activity against Gram-negative bacteria. In the present work GaS1 activity was assessed against A. fumigatus clinical isolates in a novel air-liquid-interface lung infection model, mimicking the conditions found in the CF airways. Furthermore, in this study both a solution for nebulisation and dry powders for inhalation were developed with a view to optimising GaS1 delivery to the lung. The solution for nebulisation was characterised for its osmolality and pH, while the dry powders were characterised by scanning electron microscopy, powder X-ray diffraction, thermal analysis and laser light scattering particle size analysis. The aerodynamic deposition profiles of all formulations were determined using a next generation impactor. GaS1, tested in a concentration range of 0.016-0.5 mg/mL, inhibited the growth of A. fumigatus lung isolates in a complex host-environment-mimicking medium at the non-toxic concentration of 0.063 mg/mL. A marked dose-dependent antifungal activity of GaS1 was also observed in the presence of differentiated human distal lung epithelial cells (NCI-H441) at the air liquid interface, with nearly no fungal growth detected at the macroscopic and microscopic level. A solution for nebulisation and three different dry powder inhaler formulations, prepared by spray-drying GaS1 with different concentrations of L-leucine, displayed suitable aerodynamic characteristics for GaS1 delivery to the lungs, while maintaining excellent antifungal activity. Overall, the results obtained highlight the potential of gallium-polypyridyl catecholate complexes for the management of difficult-to-treat A. fumigatus pulmonary infections.