Exploiting the potential of gallium for the treatment of Pseudomonas aeruginosa pulmonary infection

Project Summary (English) - Background Morbidity and mortality in cystic fibrosis (CF) patients is ultimately attributable to persistent pulmonary infection mainly caused by bacteria belonging to different species, the most worrisome one being Pseudomonas aeruginosa (Pa). The emergence of antibiotic resistance in CF pathogens has become a serious problem that must be addressed by developing new antimicrobials and identifying new drug targets. Gallium (Ga3+) inhibits bacterial growth, acting as an iron mimetic, and is a drug already used in clinical practice (brand name Ganite®) for the treatment of non-infectious diseases. The pharmacological properties of Ga3+ rely on the chemical resemblance between the Ga3+ and the ferric (Fe3+) ions. - Hypothesis and objectives Bacterial cells are unable to discriminate between these two ions, and erroneously incorporates Ga3+ instead of Fe3+ within essential molecules, resulting in suppression of bacterial growth. The main aims of this project is to: i) generate new gallium complexes with pyochelin-based deriovatives; ii) perform a comparative evaluation of the antibacterial activity of Ga(III) complexes/formulations against CF pathogens, and to investigate the toxicology and pharmacokinetics of the Ga(III) complexes/formulations. - Material, patients, methods We shall capitalize upon expertise in organic synthesis, pharmaceutical chemistry, microbiology and pharmacology to: i) synthesize gallium complexes ex novo; ii) evaluate the effect of Ga(III) complexes/formulations on CF pathogens; iii) determine their toxicity and pharmacological properties. In this project, the antibacterial properties of Ga3+ will be potentiated by conjugation with ligands that facilitate the stability/solubility, in order to lower the therapeutic dosage. The pharmacological activities of the new compounds will be assessed by: i) inhibition of CF-pathogens growth in vitro; ii) lack of toxicity in cellular and animal systems; iii) evaluation of biodistribution in animal models. - Expected results and spin-offs We expect to identify new Ga3+ formulations endowed with more potent antibacterial properties, high bioavailability, low toxicity and suited for aerosol administration, thus ready for clinical testing. In the worrying scenario of increasing antibiotic resistance CF pathogens, the identification of new antimicrobials such as gallium-based compounds, is highly desirable. These compounds hold great promise for the progression into drugs with potential clinical applicability in the short-medium perspective.