New drugs are needed to treat the two most prevalent Multidrug resistant (MDR) pathogens in people with cystic fibrosis (PwCF): Pseudomonas aeruginosa and Staphylococcus aureus. This is particularly important since these bacteria are able to cause chronic infections in adults and children despite the development of implemented strategies to prevent their acquisition and of early eradication therapies, thus impairing the life quality of PwCF. Within this project, we propose to apply an innovative approach, the Virtual Screening (VS), to identify bactericidal molecules with a mechanism of action different from the one of antibiotics in clinical use in order to avoid resistance. We will focus our attention on proteins involved in cell division which are essential for bacterial survival. VS is a fast and cheap method to select small molecules effective in the inhibition of the target proteins. During the VS, millions of compounds are automatically evaluated by filter rules. As much accurate are the filter rules as much higher is the successful rate of the VS.

After selecting a small number of molecules, a biological evaluation will be performed, saving time and costs to research. In particular, we will evaluate the activity of the identified compounds on the target proteins, their efficacy in inhibiting bacterial growth, and the toxicity on human cells. After obtaining these data, the compounds could be optimized from the chemical point of view to improve their activity and/or their safety profile. The compound showing the best properties will be tested in vivo, first in the wax moth Galleria mellonella, and finally in a mouse model of P. aeruginosa and S. aureus infection. The complete experimental plan will be pursued to identify new compounds effective against P. aeruginosa. At the same time, a compound already identified by our research group by VS and effective against S. aureus will be optimized and tested in vivo. Our final goal is to identify new therapeutic solutions against the two MDR pathogens that mostly affect people with CF, with a new mechanism of action with respect to currently used drugs. This will allow PwCF to improve their lifetime and the quality of life. In the future the same approach could be applied to other proteins and bacteria to find new therapeutic solutions for airway pathogens, thus promoting the introduction of innovative treatments for PwCF.