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Review
. 2024 Aug 6;63(15):1877-1891.
doi: 10.1021/acs.biochem.4c00276. Epub 2024 Jul 23.

Siderophores: A Case Study in Translational Chemical Biology

Andrew R LeBlanc  1 , William M Wuest  1
Affiliations
Review

Siderophores: A Case Study in Translational Chemical Biology

Andrew R LeBlanc et al. Biochemistry. .

Abstract

Siderophores are metal-binding secondary metabolites that assist in iron homeostasis and have been of interest to the scientific community for the last half century. Foundational siderophore research has enabled several translational applications including siderophore-antibiotic and siderophore-peptide conjugates, identification of new antimicrobial targets, advances in disease imaging, and novel therapeutics. This review aims to connect the basic science research (biosynthesis, cellular uptake, gene regulation, and effects on homeostasis) of well-known siderophores with the successive translational application that results. Intertwined throughout are connections to the career of Christopher T. Walsh, his impact on the field of chemical biology, and the legacy of his trainees who continue to innovate.

Keywords: antibiotics; natural products; secondary metabolites; siderophores.

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Conflict of interest statement

The authors declare no competing financial interest.

Figures

Figure 1
Figure 1
Siderophore overview. a) Highlighting the different classes of siderophores and b) their cellular intake, biosynthesis, and effect on different cellular processes. Abbr. TCA, tricarboxylic acid; ROS, reactive oxygen species.
Figure 2
Figure 2
a) Structure of desferrioxamine B (DFO B) and its binding mode with iron. b) The biosynthesis of DFO B precursors. c) Synthesis of DFO B originating at the N-terminus.
Figure 3
Figure 3
Structure of the naturally occurring albomycin natural product which possesses a siderophore, a cleavable serine linker, and active thioribosyl pyrimidine.
Figure 4
Figure 4
Strategically designed desferrioxamine B-ciprofloxacin SACs with a trimethyl lock linker to increase the rate of release.
Figure 5
Figure 5
Examples of oxazoline/thiazoline siderophores.
Figure 6
Figure 6
Biosynthesis of pyochelin, highlighting the shunt products isolated.
Figure 7
Figure 7
a) Related acinetobactin siderophores. b) Divergent biosynthesis of acinetobactin from the same enzymatic assembly line.
Figure 8
Figure 8
a) The pH dependent cyclization of Pseusomonine described by Wencewicz. b) Rate of cyclization based on electronics.
Figure 9
Figure 9
Biosynthesis of staphyloferrin A and related gene cluster.
Figure 10
Figure 10
Complex relationship between the building blocks of staphyloferrin B, iron concentration, and the TCA cycle suggesting additional enzymatic machinery is necessary to synthesis α-KG, L-DAP, and citric acid under limited iron conditions.
Figure 11
Figure 11
Final biosynthetic steps in the biosynthesis of staphyloferrin B highlighting the PLP-dependent decarboxylation of citryl-L-DAP by SbnH.
Figure 12
Figure 12
Citrate-ciprofloxacin SACs activity and calculated binding energy.
Figure 13
Figure 13
Cellular uptake of the enterobactin-iron complex highlighting the TonB plug within FepA.
Figure 14
Figure 14
a) Three step biosynthesis of DHB and loading DHB onto EntB. b) The enzymatic assembly line for the synthesis of enterobactin. The biosynthetic gene cluster encoding for enterobactin. (Abbreviations: peptide carrier protein (PCP), adenylation (A). condensation (C), epimerization, and thioesterase (TE). C) The gene clusters encoding for Ent.
Figure 15
Figure 15
Enterobactin and synthetic Enterobactin mimics.
Figure 16
Figure 16
a) Enterobactin-antibiotic conjugates developed in the Nolan Lab. b) Clinical siderophore based candidates.
Figure 17
Figure 17
a) Siderophore-gallium complex as an imaging agent. b) Siderophore-ruthenium complex for selective prodrug release.
See this image and copyright information in PMC

References

    1. Schneider Y. K. Bacterial Natural Product Drug Discovery for New Antibiotics: Strategies for Tackling the Problem of Antibiotic Resistance by Efficient Bioprospecting. Antibiotics 2021, 10 (7), 842. 10.3390/antibiotics10070842. - DOI - PMC - PubMed
    1. Lu L.; Hu W.; Tian Z.; Yuan D.; Yi G.; Zhou Y.; Cheng Q.; Zhu J.; Li M. Developing Natural Products as Potential Anti-Biofilm Agents. Chin Med. 2019, 14 (1), 11. 10.1186/s13020-019-0232-2. - DOI - PMC - PubMed
    1. Zhang J.; Li X.; Olmedo M.; Holdorf A. D.; Shang Y.; Artal-Sanz M.; Yilmaz L. S.; Walhout A. J. M. A Delicate Balance between Bacterial Iron and Reactive Oxygen Species Supports Optimal C. Elegans Development. Cell Host & Microbe 2019, 26 (3), 400–411.e3. 10.1016/j.chom.2019.07.010. - DOI - PMC - PubMed
    1. Walsh C. T Chemical Biology: Here to Stay?. Israel Journal of Chemistry 2019, 59, 7–17. 10.1002/ijch.201800004. - DOI
    1. Walsh C. Suicide Substrates: Mechanism-Based Enzyme Inactivators. Tetrahedron 1982, 38 (7), 871–909. 10.1016/0040-4020(82)85068-0. - DOI

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