IRON CHELATES BIND NITRIC-OXIDE AND DECREASE MORTALITY IN AN EXPERIMENTAL-MODEL OF SEPTIC SHOCK

The hydroxamic acid siderophore ferrioxamine B [Fe-III(HDFB)(+)] and t he iron complex of diethylenetriaminepentaacetic acid [Fe-III(DTPA)(2- )] protected mice against death by septic shock induced by Corynebacte rium parvum + lipopolysaccharide. Although Fe-III(DTPA)(2-) aas somewh at more effective than Fe-III(HDFB)(+), the iron-free ligand H4DFB+ wa s significantly more effective than DTPA. The hydroxamic acid chelator has a much higher iron affinity than the amine carboxylate, allowing for more efficient formation of the Fe-III(HDFB)(+) complex upon admin istration of the iron-free ligand. Electrochemical studies show that F e-III-(DTPA)(2-) binds NO stoichiometrically upon reduction to iron(II ) at biologically relevant potentials to form a stable NO adduct, In c ontrast, Fe-III(HDFB)(+) is a stable and efficient electrocatalyst for the reduction of NO to N2O at biologically relevant potentials, These results suggest that the mechanism of protection against death by sep tic shock involves NO scavenging and that particularly effective drugs that operate a low dosages may be designed based on the principle of redox: catalysis. These complexes constitute a new family of drugs tha t rely on the special ability of transition metals to activate small m olecules, In addition, the wealth of information available on sideroph ore chemistry and biology pro,ides an intellectual platform for furthe r development.