Each year, antibiotic-resistant germs cause at least 700,000 deaths worldwide. Among them, P. aeruginosa, involved in nosocomial infections, belongs to the first list of antibiotic-resistant “priority pathogens” described by the WHO. Alarmingly, the number of pan-drug-resistant specimen, untreatable with any of the antipseudomonal antibiotics available in the clinic, has increased. The double layered cell envelope of P. aeruginosa is responsible for a decreased penetration and low activity of many antibiotics.

An innovative idea to bypass this barrier relies on the siderophore‑dependent active iron uptake with a “Trojan Horse” strategy. These specific systems may allow introduction of antibacterial agents such as toxic gallium complexes. Gallium has similar atomistic characteristics to iron and can be internalized by bacteria as siderophore analog-Ga(III) complexes competing with the corresponding siderophore analog‑Fe(III) complexes. Once inside the bacteria, gallium, which cannot be reduced, blocks the bacteria's iron-dependent biological mechanisms.

A citrate-buffered gallium nitrate solution (FDA-approved, 1991) has shown promising results for the treatment of P. aeruginosa in patients with cystic fibrosis (phase 2, 2019). A low flow intravenous treatment must be used to prevent nephrotoxicity. Vectorization of gallium by siderophore analog might overcome this undesirable side effect.

Recently, we have synthesized two piperazine-based siderophore analogs bearing catechol and hydroxypyridinone ligands. In order to confirm their ability to take iron transport pathways, the physicochemical properties and the siderophore-like effect of the corresponding iron complexes have been evaluated on P. aeruginosa strains. Moreover, characterization and antipseudomonal activity were carried out for the corresponding gallium complexes.