Siderophores are low-molecular-weight organic molecules biosynthesized by bacteria and fungi optimised by nature to complex Fe(III) as part of microbial iron supply [1,2]. As natural product chelators, siderophores have inherent structural complexity beyond synthetic ‘off-the-shelf’ chelators, which prompted our thinking to use siderophores as a springboard to expand even further the chemical space of chelators and by extension, potential metal binding applications in biomedicine and the environment. We selected the trihydroxamic acid desferrioxamine B (DFOB) to develop our chemical/biological engineering approaches, as supported by foundational knowledge of its biosynthesis [3-5], its production by many actinomycetes species, and its clinical and pre-clinical presence for secondary iron overload disease and immunological positron emission tomography (PET) imaging, respectively [6]. Here, I will describe approaches where we blended methods in microbiology and semi-synthetic chemistry [7-9], organic and supramolecular chemistry [10], organic and inorganic chemistry [11], or chemo-enzymology and medicinal chemistry [12] to generate DFOB analogues with new properties, coordination chemistry, and potential applications. Alongside these methodological and application-driven goals, we have expanded fundamental understanding of siderophore biosynthesis and its control, and proposed new mechanistic and functional insight [12,13]. The cross-discipline methods we have developed to expand chemical space and property/function diversity for this single class of natural product chelator could be transferred to other secondary metabolites relevant to bioinorganic chemistry and beyond.
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