Summary: In order to get access to iron, Pseudomonas aeruginosa strain PAO1 produces two major siderophores pyoverdine (PVD) and pyochelin (PCH). Both siderophores are able to chelate many other metals in addition to iron. However, despite this property, only iron is transported efficiently into the bacteria by the PVD and PCH uptake pathways. Growth studies with P. aeruginosa strains showed a lower sensitivity to toxic metals for the siderophore‐producing strain than for the mutants unable to produce siderophores. Moreover, addition of PVD or PCH to the growth medium of a siderophore‐deficient strain considerably reduced the toxicity of toxic metals present at concentrations of 100 µM in iron‐limited and iron‐supplemented growth conditions. Measurement by Inductively Coupled Plasma‐Atomic Emission Spectrometry of the concentration of metals present in bacteria incubated with metals in the presence or absence of PVD or PCH indicated that both siderophores were able to sequester metals from the extracellular medium of the bacteria, decreasing metal diffusion into the bacteria. Pyoverdine was able to sequester Al ³⁺ , Co ²⁺ , Cu ²⁺ , Eu ³⁺ , Ni ²⁺ , Pb ²⁺ , Tb ³⁺ and Zn ²⁺ from the extracellular medium, and PCH, Al ³⁺ , Co ²⁺ , Cu ²⁺ , Ni ²⁺ , Pb ²⁺ and Zn ²⁺ . Moreover, the presence of 100 µM Cu ²⁺ and Ni ²⁺ increased PVD production by 290% and 380%, respectively, in a medium supplemented with iron. All these data suggest that PVD and PCH may contribute to P. aeruginosa resistance to heavy metals.

Pseudomonas aeruginosa is a Gram-negative opportunistic pathogen responsible for nosocomial infections. The prevalence of antibiotic-resistant P. aeruginosa strains is increasing, necessitating the urgent development of new strategies to improve the control of this pathogen. Its bacterial envelope constitutes of an outer and an inner membrane enclosing the periplasm. This structure plays a key role in the resistance of the pathogen, by decreasing the penetration and the biological impact of many antibiotics. However, this barrier may also be seen as the “Achilles heel” of the bacterium as some of its functions provide opportunities for breaching bacterial defenses. Siderophore-dependent iron uptake systems act as gates in the bacterial envelope and could be used in a “Trojan horse” strategy, in which the conjugation of an antibiotic to a siderophore could significantly increase the biological activity of the antibiotic, by enhancing its transport into the bacterium. In this review, we provide an overview of the various siderophore–antibiotic conjugates that have been developed for use against P. aeruginosa and show that an accurate knowledge of the structural and functional features of the proteins involved in this transmembrane transport is required for the design and synthesis of effective siderophore–antibiotic Trojan horse conjugates.