bidentate ligands per molecule, forming a hexadentate complex and causing a smaller entropic change than that caused by chelating a single ferric ion with separate ligands. Fe3+ is a strong Lewis acid, preferring strong Lewis bases such as anionic or neutral oxygen atoms to coordinate with. Microbes usually release the iron from the siderophore by reduction to Fe2+ which has little affinity to these ligands. Siderophores are usually classified by the ligands used to chelate the ferric iron. The major groups of siderophores include the catecholates (phenolates), hydroxamates and carboxylates (e.g. derivatives of citric acid). Citric acid can also act as a siderophore. The wide variety of siderophores may be due to evolutionary pressures placed on microbes to produce structurally different siderophores which cannot be transported by other microbes' specific active transport systems, or in the case of pathogens deactivated by the host organism. Diversity Examples of siderophores produced by various bacteria and fungi: Hydroxamate siderophores Catecholate siderophores Mixed ligands Amino carboxylate ligands A comprehensive list of siderophore structures (over 250) is presented in Appendix 1 in reference. Biological function Bacteria and fungi In response to iron limitation in their environment, genes involved in microbe siderophore production and uptake are derepressed, leading to manufacture of siderophores and the appropriate uptake proteins. In bacteria, Fe2+-dependent repressors bind to DNA upstream to genes involved in siderophore production at high intracellular iron concentrations. At low concentrations, Fe2+ dissociates from the repressor, which in turn dissociates from the DNA, leading to transcription of the genes. In gram-negative and AT-rich gram-positive bacteria, this is usually regulated by the Fur (ferric uptake regulator) repressor, whilst in GC-rich gram-positive bacteria (e.g. Actinomycetota) it is DtxR (diphtheria toxin repressor), so-called as the production of the dangerous diphtheria toxin by Corynebacterium diphtheriae is also regulated by this system. This is followed by excretion of the siderophore into the extracellular environment, where the siderophore acts to sequester and solubilize the iron. Siderophores are then recognized by cell specific receptors on the outer membrane of the cell. In fungi and other eukaryotes, the Fe-siderophore complex may be extracellularly reduced to Fe2+, while in many cases the whole Fe-siderophore complex is actively transported across the cell membrane. In gram-negative bacteria, these are transported into the periplasm via TonB-dependent receptors, and are transferred into the cytoplasm by ABC transporters. Once in the cytoplasm of the cell, the Fe3+-siderophore complex is usually reduced to