Iron chelates bind nitric oxide and decrease mortality in an experimental model of septic shock.
The hydroxamic acid siderophore ferrioxamine B [FeIII(HDFB)+] and the iron complex of diethylenetri-aminepentaacetic acid [FeIII(DTPA)2-] protected mice against death by septic shock induced by Corynebacterium parvum + lipopolysaccharide. Although FeIII(DTPA)2- was somewhat more effective than FeIII(HDFB)+, the iron-free ligand H4DFB+ was 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 FeIII(HDFB)+ complex upon administration of the iron-free ligand. Electrochemical studies show that FeIII(DTPA)2- binds NO stoichiometrically upon reduction to iron(II) at biologically relevant potentials to form a stable NO adduct. In contrast, FeIII(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 septic 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 that rely on the special ability of transition metals to activate small molecules. In addition, the wealth of information available on siderophore chemistry and biology provides an intellectual platform for further development.
Kazmierski
W M
WM
Division of Organic Chemistry, Burroughs Wellcome, Research Triangle Park, NC 27709, USA.
Wolberg
G
G
Wilson
J G
JG
Smith
S R
SR
Williams
D S
DS
Thorp
H H
HH
Molina
L
L
D000818:Animals; D003354:Corynebacterium Infections / Q000188:drug therapy; D003676:Deferoxamine / Q000378:metabolism / Q000627:therapeutic use*; D004553:Electric Conductivity; D005290:Ferric Compounds / Q000378:metabolism / Q000627:therapeutic use*; D007502:Iron Chelating Agents / Q000378:metabolism / Q000627:therapeutic use*; D008297:Male; D051379:Mice; D009569:Nitric Oxide / Q000378:metabolism*; D004369:Pentetic Acid / Q000031:analogs & derivatives* / Q000378:metabolism / Q000627:therapeutic use; D011425:Propionibacterium acnes; D012772:Shock, Septic / Q000188:drug therapy* / Q000401:mortality
D005290:Ferric Compounds; D007502:Iron Chelating Agents; C061309:DTPA ferric chelate; D009569:Nitric Oxide; C002577:ferrioxamine B; D004369:Pentetic Acid; D003676:Deferoxamine