Iron-Chelating Agents

IRON-CHELATING AGENTS

The growth of many microorganisms in iron-deficient growth media results in the secretion of low molecular weight iron-chelating agents called siderophores, which are usually phenolate or hydroxamate compounds. The therapeutic potential of these compounds has generated considerable interest. Uncomplicated iron deficiency can be treated with oral preparations of iron(II) (ferrous) sulphate but such treatment is not without hazard and iron salts remain a common cause of poisoning in children. The accidental consumption of around 3 g of ferrous sulphate by a small child leads to acidosis, coma and heart failure which, if untreated, are fatal. Desferrioxamine B (Figure 26.2), the deferrated form of a siderophore produced by Streptomyces pilosus, is a highly effective antidote for the treatment of acute iron poisoning. Desferrioxamine owes its effectiveness both to its high affinity for ferric iron (its binding constant is in excess of 10 ³⁰) and because the iron–desferrioxamine complex is highly water-soluble and is readily excreted through the kidneys. In haemolytic anaemias such as thalassaemia, desferrioxamine is used together with blood transfusions to maintain normal blood levels of free iron and haemoglobin. Desferrioxamine is prepared as a sterile powder for use as an injection, but it is also administered orally in acute iron poisoning to remove unabsorbed iron from the gut.

Patients with iron overload disorders treated with desferrioxamine may, however, have increased susceptibility to infections. The important role played by iron availability during infections in vertebrate hosts has only been recognized relatively recently. The ability of the host to withhold growth-essential iron from microbial and, indeed, neo-plastic invaders while retaining its own access to this metal has led to suggestions that microbial iron chelators or their semisynthetic derivatives may be of use in antimicrobial and anticancer chemotherapy. Preliminary work has shown some encouraging results. The bacterial siderophores parabactin and compound II secreted by Paracoccus denitrificans have been shown to inhibit the growth of leukaemia cells in culture and in experimental animals. They also appear capable of inhibiting the replication of RNA viruses. Siderophores such as desferrioxamine may therefore find increasing applications not only in the treatment of iron poisoning and iron-overloaded disease states but also as chemotherapeutic agents.