Assessment of structural features of the Pseudomonas siderophore pyochelin required for its ability to promote oxidant-mediated endothelial cell injury

We previously showed that iron chelated to the Pseudomonas aeruginosa siderophore pyochelin enhances oxidant-mediated injury to pulmonary artery endothelial cells by catalyzing hydroxyl radical (HO) formation. Therefore, we examined pyochelin structural/chemical features that may be important in this process. Five pyochelin analogues were examined for (i) capacity to accentuate oxidant-mediated endothelial cell injury, (ii) HO catalytic ability, (iii) iron transfer to endothelial cells, and (iv) hydrophobicity. All compounds catalyzed similar HO. Production, but only the hydrophobic ones containing a thiazolidine ring enhanced cell injury. Transfer of iron to endothelial cells did not correlate with cytotoxicity. Finally, binding of Fe³⁺ by pyochelin led to Fe²⁺ formation, perhaps explaining how Fe³⁺-pyochelin augments H₂O₂-mediated cell injury via HO formation. The ability to bind iron in a catalytic form and the molecule’s thiazolidine ring, which increases its hydrophobicity, are key to pyochelin’s cytotoxicity. Reduction of Fe³⁺ to Fe²⁺ may also be important.