Zinc homeostasis: a promising target for novel anti-Pseudomonas therapies in Cystic Fibrosis

Pseudomonas aeruginosa, one of the most dangerous pathogens for patients with Cystic Fibrosis, displays an exceptional ability to acquire zinc in environments poor of this metal. Unlike many other Gram-negative bacteria that are able to import zinc essentially through a unique high affinity zinc importer, ZnuABC, P. aeruginosa possesses redundant metal uptake systems. We have found that inactivation of the main zinc importers severely impacts on P. aeruginosa ability to cause acute lung and systemic infections in mice, likely due to the involvement of zinc in the expression of several virulence traits. Virulence features depending on zinc intake include the release of active extracellular zinc-containing proteases, the capability to produce flagella and the ability to synthesize the biofilm-associated exopolysaccharide alginate. Furthermore zinc deficiency represses genes involved in the synthesis of the siderophore pyoverdine, thereby suggesting that zinc recruitment hierarchically modulates iron uptake. In view of the fact that recent studies have shown that it is possible to pharmacologically target zinc homeostasis in pathogenic microorganisms, the characterization of the mechanisms of zinc uptake and the identification of the crucial role of this metal in bacterial pathogenicity suggest promising possibilities to combat this pathogen.