Chronic lung infections caused by Pseudomonas aeruginosa are among the primary complications of cystic fibrosis (CF), partly due to the increasing resistance of these bacteria to antibiotics. 

A key factor in their ability to thrive in the lung environment is their remarkable capacity to acquire zinc (Zn), a metal essential for many cellular functions. The human immune system attempts to limit bacterial access to zinc to inhibit their growth, but P. aeruginosa has developed sophisticated systems to capture it from its surroundings using molecules called zincophores.

The project, a continuation of the previous project FFC#4/2023, aims to exploit this zinc uptake pathway to develop a therapeutic strategy based on the “Trojan horse” concept. This approach involves binding an antibiotic to a molecule that mimics the natural zinc transporters used by bacteria, allowing the drug to enter bacterial cells more effectively and overcome their defences, including those that cause resistance to traditional treatments.

A new antibiotic called aztreopine has recently been developed by combining aztreonam -an antibiotic already used in clinical practice- with a portion of pseudopalin, the zinc transporter used by P. aeruginosa.

The researchers aim to validate the efficacy of aztreopine on a wide range of clinical variants of P. aeruginosa isolated from people with CF, verifying its activity even against strains resistant to conventional antibiotics. Additionally, its efficacy will also be tested in vivo using animal models of lung infection (thanks to the CFaCore service provided by FFC Ricerca) along with an evaluation of its toxicity. 
In parallel, efforts will focus on developing new conjugates targeting P. aeruginosa.

This research could revolutionise the treatment of lung infections in CF, offering new therapeutic options that are effective even against multi-resistant strains and improving the management of chronic infections.