Oral Presentation Royal Australian Chemical Institute National Congress 2026

Diversifying production methods for the clinical natural product desferrioxamine B (136477)

Todd E Markham 1 , Athavan Sresutharsan 1 , Callum A Rosser 1 , Rachel Codd 1
  1. School of Medical Sciences, The University of Sydney, Camperdown, NSW, Australia

Microbes generate secondary metabolites for iron sequestration known as siderophores. These low molecular weight natural products bind ferric iron (Fe3+) with high specificity and affinity, overcoming the poor bioavailability of iron in the environment.1, 2 Desferrioxamine B (DFOB) is a hydroxamic acid-bearing siderophore with ongoing clinical use as an iron chelator for treating iron overload. DFOB is recognized by the World Health Organisation as an essential medicine for its ongoing use in chelation therapy for acute iron toxicity and secondary iron overload in blood transfusion-dependent disorders like β-thalassemia.3 DFOB has more recently become known for its application in the development of radiopharmaceutical imaging agents as a chelator for zirconium-89, an import moiety for Trojan horse antibiotic strategies, and as a tool in chemical biology to explore microbial metabolite production and proteomes. Commercial production of DFOB relies on industrial scale fermentation of Streptomyces pilosus and is limited by co-production of other hydroxamic siderophores, requiring rigorous purification processes to access a clinical grade product. Diversifying production methods beyond traditional fermentation may offer alternatives that overcome the limitation of this whole-cell approach.

Our recent work has investigated two distinct approaches to diversify the production of DFOB as a single isolable product. We have developed a mild total synthetic approach, that overcomes the chemoselectivity and safety concerns of previous attempts, with commercial potential and modularity that opens avenues for structural diversification.4 In addition, we have investigated a biocatalytic approach leveraging the final enzyme in the DFOB biosynthetic pathway. Using a non-ribosomal peptide synthetase-independent siderophore synthetase from Salinispora tropica (StDesD) and chemically protected substrates we were able to direct the assembly of DFOB to a single chemoenzymatic product that can be readily deprotected in situ to furnish the clinical natural product.5

  1. Codd, R. 2.02 - Siderophores and iron transport. In Comprehensive Inorganic Chemistry III, Pecoraro, V. L., Guo, Z. Eds.; Vol. 2; Elsevier, 2023; pp 3-29.
  2. Sandy, M.; Butler, A. Microbial Iron Acquisition: Marine and Terrestrial Siderophores. Chem. Rev. 2009, 109 (10), 4580-4595.
  3. Codd, R.; Richardson-Sanchez, T.; Telfer, T. J.; Gotsbacher, M. P. Advances in the Chemical Biology of Desferrioxamine B. ACS Chem. Biol. 2018, 13, 11-25.
  4. Markham, T. E.; Codd, R. A Mild and Modular Approach to the Total Synthesis of Desferrioxamine B. J. Org. Chem. 2024, 89 (7), 5118-5125. DOI: 10.1021/acs.joc.3c02739.
  5. Markham, T. E.; Sresutharsan, A.; Rosser, C. A.; Codd, R. Directing the chemoenzymatic assembly of desferrioxamine B as a single product using N-tert-butoxycarbonyl-protected substrates. Org. Biomol. Chem. 2025, 23, 7181-7187.