Lung infections caused by Pseudomonas aeruginosa pose a serious threat to people with cystic fibrosis (CF) and the danger is further aggravated by the increasing prevalence of antibiotic-resistant variants. 
Very few new antibiotics have been developed in recent decades: one approach is to aim to improve the efficacy of those already available.

The virulence of P. aeruginosa depends significantly on its ability to import zinc from the extracellular environment, via a zinc-transporting molecule called pseudopaline. 
In this project, the researchers therefore exploited pseudopaline as a ‘Trojan horse’ to import an antibiotic into the bacterium: chemical synthesis strategies were developed to produce modified forms of pseudopaline, and two of these molecules were obtained in a form conjugated to the antibiotic aztreonam, which is often used to treat pulmonary infections in CF.

The study was conducted mainly on reference variants of P. aeruginosa, i.e. bacteria cultivated in the laboratory, and validated on an initial collection of clinical isolates of the bacterium, and the antimicrobial activity of the conjugated forms obtained was tested on bacteria cultured both in the presence and absence of zinc.
Molecules formed from conjugates of pseudopaline and aztreonam showed clear antimicrobial activity against reference variants of P. aeruginosa and were seen to enter the cell via the receptor for pseudopaline. One of these conjugates has much higher activity than the antibiotic aztreonam alone, both against reference variants and the clinical isolates tested. Thanks to these results, it was possible to develop a modified antibiotic that is more active than the original in vitro. 

The researchers intend to proceed with patent protection of the modified antibiotic. The efficacy of the molecule will be evaluated on a larger collection of clinical isolates, including aztreonam-resistant bacteria, and in animal models.

Abstracts submitted to scientific conferences

• Exploring metallophore-antibiotic conjugates as a novel antimicrobial strategy that exploits Pseudomonas aeruginosa zinc dependence. XXVIII National Congress of the Società Chimica Italiana, Milan, Italy, 26-30 August 2024
• Exploring metallophore-antibiotic conjugates as a novel antimicrobial strategy that exploits Pseudomonas aeruginosa zinc dependence. EMFC-ISMC, International symposium on medicinal chemistry, Rome, Italy, 1-5 September 2024
• Exploring a novel Trojan horse strategy to treat Pseudomonas aeruginosa infections. International Biennial Pseudomonas Conference, Pseudomonas 2024, Copenhagen, Denmark, 1-6 September 2024