Beyond iron: non-classical biological functions of bacterial siderophores

Abstract

Bacteria secrete small molecules known as siderophores to acquire iron from their surroundings. For over 60 years, investigations into the bioinorganic chemistry of these molecules, including fundamental coordination chemistry studies, have provided insight into the crucial role that siderophores play in bacterial iron homeostasis. The importance of understanding the fundamental chemistry underlying bacterial life has been highlighted evermore in recent years because of the emergence of antibiotic-resistant bacteria and the need to prevent the global rise of these superbugs. Increasing reports of siderophores functioning in capacities other than iron transport have appeared recently, but reports of "non-classical" siderophore functions have long paralleled those of iron transport. One particular non-classical function of these iron chelators, namely antibiotic activity, was documented before the role of siderophores in iron transport was established. In this Perspective, we present an exposition of past and current work into non-classical functions of siderophores and highlight the directions in which we anticipate that this research is headed. Examples include the ability of siderophores to function as zincophores, chalkophores, and metallophores for a variety of other metals, sequester heavy metal toxins, transport boron, act as signalling molecules, regulate oxidative stress, and provide antibacterial activity.

Figure 1

Ball-and-stick representations of the metal complexes from the crystal structures of (A) yersiniabactin-Fe(III) (CCDC ID: 619878) and (B) micacocidin-Zn(II) (micacocidin A, CCDC ID: 130920). Non-polar hydrogen atoms have been omitted for clarity. Colour code: C gray, O red, N blue, H white, Fe orange, and Zn green.

Figure 2

Thermal ellipsoid diagrams from the crystal structures of the (A) vanadium and (B) silicon complexes of enterobactin (CCDC ID: 624678 and 920703, respectively).^, Thermal ellipsoids are drawn at the 50% probability level and hydrogen atoms are shown as spheres of arbitrary radius. Colour code: C gray, O red, N blue, V purple, and Si green.

Figure 3

Lipocalin-2 bound to either (A) hydrolyzed or (B) non-hydrolyzed ferric enterobactin (PDB ID: 3BY0 and 3CMP, respectively). (C) Non-hydrolyzed ferric enterobactin complexed with FeuA (PDB ID: 2XUZ). In all panels, the protein is shown as a wheat-coloured surface. The ligands of the protein-bound small molecule are shown as sticks and the iron atom as a sphere. Colour code: C grey, O red, N blue, and Fe orange.

Figure 4

Ball-and-stick representations of the metal complexes from the crystal structures of (A) [Fe(pdtc)₂]⁻ (NBS ID: 557651), (B) [Co(pdtc)₂]⁻ (NBS ID: 596508), and (C) [Ni(pdtc)₂]²⁻ (NBS ID: 596506). Colour code: C gray, O red, N blue, H white, Fe orange, Co pink, and Ni green.

Figure 5

Molecular diagram of the siderophore complex from the crystal structure of desferrioxamine E-triaquaplutonium(IV) (CCDC ID: 136339). Non-hydrogen atoms are shown as shaded spheres of arbitrary radius and hydrogen atoms have been removed for clarity. Colour code: C gray, O red, N blue, and Pu orange.

Figure 6

Ball-and-stick model of the proposed structure of the vibrioferrin-borate complex. The structure was minimized with GaussView based on that depicted in reference. Color code: C gray, O red, N blue, H white, and B pink.

Chart 1

Chemical structures of the siderophores discussed in the introduction. The stereochemistry of yersiniabactin was taken from reference . The structure of salmochelin S2 is that reported in reference . An alternative structure of a linearized salmochelin S4 in which a glucosyl unit is attached at the carboxylic acid end of the linearized trimer instead of the alcohol end has also been reported. The enantiomer of the form of pyochelin shown, enantio-pyochelin, is a known siderophore. ^‡Many pyoverdines exist and are distinguished by the nature of the peptide chain attached at the R position.

Chart 2

Chemical structures of the siderophores discussed in Siderophores as Zincophores. The stereochemistry of yersiniabactin was taken from reference . ^*The structure of coelibactin is tentative and based on bioinformatics analyses; stereochemistry has yet to be established. ^†Rhizoferrin can occur as shown (S,S) or in the enantiomeric (R,R) form. ^‡Many pyoverdines exist and are distinguished by the nature of the peptide chain attached at the R position. Pdtc is pyridine-2,6-dithiocarboxylic acid.

Chart 3

Chemical structures of the siderophores discussed in Fuelling Nitrogenase: Molybdenum and Vanadium. ^‡Azotobactin has a peptide chain as the R substituent.

Chart 4

Chemical structures of the siderophores discussed in The Interaction of Siderophores with Copper. The stereochemistry of yersiniabactin was taken from reference . The enantiomer of the form of pyochelin shown, enantio-pyochelin, is a known siderophore. ^‡Many pyoverdines exist and are distinguished by the nature of the peptide chain attached at the R position. Pdtc is pyridine-2,6-dithiocarboxylic acid.

Chart 5

Chemical structures of the siderophores discussed in Other Metals: Transport and Sequestration and Marine Siderophores and Boron. The stereochemistry of yersiniabactin was taken from reference . The enantiomer of the form of pyochelin shown, enantio-pyochelin, is a known siderophore. ^‡Many pyoverdines exist and are distinguished by the nature of the peptide chain attached at the R position. ^*The stereochemistry of the delftibactins has not been reported.^{, †}The chemical structure of vibrioferrin was obtained from reference . Pdtc is pyridine-2,6-dithiocarboxylic acid.

Chart 6

Chemical structures of the siderophores discussed in Siderophores as Signalling Molecules. The stereochemistry of yersiniabactin was taken from reference . ^‡Many pyoverdines exist and are distinguished by the nature of the peptide chain attached at the R position. ^†The chemical structure of vibrioferrin was obtained from reference .

Chart 7

Chemical structures of the siderophores discussed in Protection from Oxidative Stress. The stereochemistry of yersiniabactin was taken from reference . The chemical structures of staphyloferrin A and staphyloferrin B were obtained from references ^and . The structure of salmochelin S2 is that reported in reference . An alternative structure of a linearized salmochelin S4 in which a glucosyl unit is attached at the carboxylic acid end of the linearized trimer instead of the alcohol end has also been reported.

Chart 8

Chemical structures of the siderophores discussed in Sideromycins: Siderophores as Antibiotics. The enantiomer of the form of pyochelin shown, enantio-pyochelin, is a known siderophore.

Chart 9

Natural sideromycins of known structure. The iron-binding siderophore unit is black, the antibiotic warhead is shown in red, and if a linker is present it is shown in blue. ^*It is also possible that water is added such that this position bears a gem-diol.