The introduction of CFTR modulators, such as ETI, has revolutionised the treatment of cystic fibrosis (CF), improving lung function and, indirectly, the immune system’s ability to control infections. However, this effect is not sufficient to eliminate Pseudomonas aeruginosa, one of the main causes of chronic infection. In fact, this bacterium can persist in the CF lung and resist to antibiotics thanks not only to biofilm production but also because it is able to survive inside lung epithelial cells and macrophages, immune system cells responsible for engulfing and destroying pathogens.

The project aims to target DksA, a protein previously identified by the research group, which is essential for the survival and adaptation of P. aeruginosa in the CF lung. DksA regulates numerous mechanisms that enable the bacterium to withstand stress, produce virulence factors and survive within host cells, in particular macrophages. Blocking DksA activity could therefore weaken the bacterium and make it easier for the immune system and antibiotics to eliminate it.
To identify molecules capable of inhibiting DksA, the researchers analysed thousands of drugs already approved for the treatment of other diseases not related to CF. This approach, known as drug repurposing, accelerates the development and clinical use of new therapies by utilising drugs whose safety and pharmacological properties are already well established. Fifteen promising compounds were selected from the screening and will now be studied in greater depth. The drugs will first be tested in vitro, in human CF cells infected with P. aeruginosa, both on their own and in combination with ETI, to assess whether they can enhance its effectiveness in controlling the infection.
The most effective molecules will be tested in vivo in an animal model, in collaboration with the FFC Ricerca CFaCore Facility.

The ultimate aim of the project is to identify at least one new DksA inhibitor to be developed as an adjuvant therapy, capable of reducing the adaptability and survival of P. aeruginosa and improving the control of chronic infections in people with CF.