Background. In cystic fibrosis (CF) patients, Pseudomonas aeruginosa-induced pneumonia requires frequent antibiotic treatment. Low sensitivity to many antibiotics by P. aeruginosa has prompted the search for novel drugs aimed at the specific inhibition of pathogenesis-related processes. Antimetabolite drugs, such as the pyrimidine analogue flucytosine (FC), are effective inhibitors of biofilm formation and of virulence factors’ production, and show promising activity against P. aeruginosa infections in animal models. However, their utilization in therapy is hindered by possible toxicity, occurrence of resistance, and by lack of precise information of their mechanism of action.
Hypothesis and objectives. The main hypothesis behind this work was that antimetabolite drugs other than FC could share its properties and affect P. aeruginosa virulence and persistence in the host. In addition, we wanted to establish the specific mode of action of FC, as a starting point towards the development of new drugs sharing the same mechanism of action and showing lower risks of long term toxicity.