Chemical Biology of Siderophores

Summary

Studies of bacterial metal-management strategies have implications for treating iron overload disease and for better understanding bacterial pathogenic virulence.

Supervisor(s)

Dr Rachel Codd

Research Location

Camperdown - School of Medical Sciences - Bosch Institute

Program Type

PHD

Synopsis

The survival of almost all organisms depends upon the availability of iron which is essential for the assembly of proteins that direct electron transfer (cytochromes) and DNA biosynthesis (ribonucleotide reductase). Since in an oxic, aqueous and pH-neutral environment, Fe(III) is poorly soluble (Ksp ~ 10-39), pathogenic and non-pathogenic bacteria have evolved various Fe(III) scavenging strategies, one of which involves the biosynthesis of small molecules known as siderophores (Greek “iron carrier”) that bind Fe(III) with high affinity. Siderophores are chemically diverse and feature either catecholate, hydroxamic acid or citric acid based Fe(III) binding groups. Proteins located at the bacterial cell surface or outer membrane recognise the soluble Fe(III)-siderophore complex with high specificity and actively transport the complex into the cell with the Fe ultimately released in the cytoplasm. The mesylate salt of a hydroxamate-based siderophore derived from the soil bacterium, Streptomyces pilosus, is in clinical use for the treatment of transfusional-dependent iron overload in humans, a potentially fatal complication of the genetic blood disorder, b-thalassemia. Although about 500 different types of siderophores have been documented, only a handful have been fully characterised, since these key biomolecules are produced in very small (nM) amounts in cultures of bacteria grown under iron deprivation. This multifaceted program encompasses individual projects in: (i) the isolation and characterisation of siderophores from extremophilic bacteria; (ii) novel siderophores from direct fermentation; (ii) technologies in siderophore capture; (iii) isolation of Fe(III)-siderophore recognition proteins; and (iv) drug design for iron-overload disease.

Additional Information

Techniques used in the project:

  • Metabolite purification
  • Metal binding studies
  • Semisynthesis
  • Protein purification
  • Bioinformatics

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Keywords

b-thalassemia, metals in biology, iron, siderophores, biodiscovery, purification technologies, extremophilic bacteria, Cancer & leukaemia, Therapeutics & adverse drug effects, Cell biology, Pharmacology & therapeutics

Opportunity ID

The opportunity ID for this research opportunity is: 247