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 Fe(3+) by pyochelin led to Fe(2+) formation, perhaps explaining how Fe(3+)-pyochelin augments H(2)O(2)-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 Fe(3+) to Fe(2+) may also be important.
DeWitte
J J
JJ
Department of Internal Medicine and Research Service, VA Medical Center-Iowa City, Iowa City, Iowa 52242, USA.
Cox
C D
CD
Rasmussen
G T
GT
Britigan
B E
BE
D000818:Animals; D002384:Catalysis; D002478:Cells, Cultured; D004347:Drug Interactions; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000293:injuries / Q000473:pathology; D006861:Hydrogen Peroxide / Q000378:metabolism; D017665:Hydroxyl Radical / Q000378:metabolism; D007501:Iron / Q000378:metabolism; D007502:Iron Chelating Agents / Q000737:chemistry / Q000494:pharmacology; D016877:Oxidants / Q000494:pharmacology*; D010636:Phenols / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D011550:Pseudomonas aeruginosa / Q000737:chemistry*; D013552:Swine; D013844:Thiazoles
D007502:Iron Chelating Agents; D016877:Oxidants; D010636:Phenols; D013844:Thiazoles; C025315:ferripyochelin; D017665:Hydroxyl Radical; C025316:pyochelin; D006861:Hydrogen Peroxide; D007501:Iron