Siderophores: A Case Study in Translational Chemical Biology

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.

• Publication year

  2024

• Venue

  Biochemistry

• Publication date

  2024-07-23

• Fields of study

  Biology, Medicine, Chemistry

• Identifiers
  DOI 10.1021/acs.biochem.4c00276PMID 39041827PMCID 11308372
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• Conjugation to Native and Nonnative Triscatecholate Siderophores Enhances Delivery and Antibacterial Activity of a β-Lactam to Gram-Negative Bacterial Pathogens.

  2024cited by this paper
• "Off-Label" Use of Enterobactin Enables Targeted Imaging of Cancer with Radioactive Ti(IV).

  2024cited by this paper
• Siderophore Synthetase DesD Catalyzes N-to-C Condensation in Desferrioxamine Biosynthesis.

  2023cited by this paper
• Siderophore conjugates to combat antibiotic-resistant bacteria.

  2023cited by this paper
• Siderophore‐Linked Ruthenium Catalysts for Targeted Allyl Ester Prodrug Activation within Bacterial Cells

  2022cited by this paper
• Heavy-Metal Trojan Horse: Enterobactin-Directed Delivery of Platinum(IV) Prodrugs to Escherichia coli.

  2022cited by this paper
• Trojan Horse Siderophore Conjugates Induce Pseudomonas aeruginosa Suicide and Qualify the TonB Protein as a Novel Antibiotic Target

  2022cited by this paper
• On the origin of amphi-enterobactin fragments produced by Vibrio campbellii species

  2022cited by this paper
• Bacterial Natural Product Drug Discovery for New Antibiotics: Strategies for Tackling the Problem of Antibiotic Resistance by Efficient Bioprospecting

  2021cited by this paper
• Pyochelin Biosynthetic Metabolites Bind Iron and Promote Growth in Pseudomonads Demonstrating Siderophore-like Activity.

  2021cited by this paper
• Rapid Development of Cefiderocol Resistance in Carbapenem-resistant Enterobacter cloacae During Therapy Is Associated With Heterogeneous Mutations in the Catecholate Siderophore Receptor cirA

  2021cited by this paper
• Cefiderocol: A Review in Serious Gram-Negative Bacterial Infections

  2021cited by this paper
• Hierarchical routing in carbon metabolism favors iron-scavenging strategy in iron-deficient soil Pseudomonas species

  2020cited by this paper
• Structural insights into substrate recognition and activity regulation of the key decarboxylase SbnH in staphyloferrin B biosynthesis.

  2019cited by this paper
• Developing natural products as potential anti-biofilm agents

  2019cited by this paper
• In Vitro Activity of Cefiderocol Against a Broad Range of Clinically Important Gram-negative Bacteria

  2019cited by this paper
• Pyonitrins A–D: Chimeric Natural Products Produced by Pseudomonas protegens

  2019cited by this paper
• A Delicate Balance between Bacterial Iron and Reactive Oxygen Species Supports Optimal C. elegans Development.

  2019cited by this paper
• Siderophore–Antibiotic Conjugate Design: New Drugs for Bad Bugs?

  2019cited by this paper
• Interdependence between iron acquisition and biofilm formation in Pseudomonas aeruginosa

  2018cited by this paper
• Chemical Biology: Here to Stay?

  2018cited by this paper
• Pharmacokinetics, Safety, and Tolerability Evaluation of Single and Multiple Doses of GSK3342830 in Healthy Volunteers

  2018cited by this paper
• Redox-switchable siderophore anchor enables reversible artificial metalloenzyme assembly

  2018cited by this paper
• Natural products from thioester reductase containing biosynthetic pathways.

  2018cited by this paper
• Chemical Activation in Blood Serum and Human Cell Culture: Improved Ruthenium Complex for Catalytic Uncaging of Alloc‐Protected Amines

  2017cited by this paper
• Bacterial Iron Uptake Pathways: Gates for the Import of Bactericide Compounds.

  2017cited by this paper
• Key Structural Elements for Cellular Uptake of Acinetobactin, a Major Siderophore of Acinetobacter baumannii.

  2017cited by this paper
• Structure-function studies of acinetobactin analogs.

  2017cited by this paper
• Acinetobactin Isomerization Enables Adaptive Iron Acquisition in Acinetobacter baumannii through pH-Triggered Siderophore Swapping.

  2016cited by this paper
• Insights into the chemical logic and enzymatic machinery of NRPS assembly lines.

  2016cited by this paper
• Deciphering the Substrate Specificity of SbnA, the Enzyme Catalyzing the First Step in Staphyloferrin B Biosynthesis

  2016cited by this paper
• Siderophores for molecular imaging applications

  2016cited by this paper
• Chemical Synthesis of Staphyloferrin B Affords Insight into the Molecular Structure, Iron Chelation, and Biological Activity of a Polycarboxylate Siderophore Deployed by the Human Pathogen Staphylococcus aureus.

  2015cited by this paper
• Probing linker design in citric acid-ciprofloxacin conjugates.

  2014cited by this paper
• Enterobactin-Mediated Delivery of β-Lactam Antibiotics Enhances Antibacterial Activity against Pathogenic Escherichia coli

  2014cited by this paper
• Regulation of iron transport systems in Enterobacteriaceae in response to oxygen and iron availability.

  2014cited by this paper
• Structure Revision of N-Mercapto-4-formylcarbostyril Produced by Pseudomonas fluorescens G308 to 2-(2-Hydroxyphenyl)thiazole-4-carbaldehyde [aeruginaldehyde]

  2014cited by this paper
• TCA cycle activity in Staphylococcus aureus is essential for iron‐regulated synthesis of staphyloferrin A, but not staphyloferrin B: the benefit of a second citrate synthase

  2014cited by this paper
• Synthesis of L-2,3-diaminopropionic acid, a siderophore and antibiotic precursor.

  2014cited by this paper
• Staphyloferrin A as siderophore-component in fluoroquinolone-based Trojan horse antibiotics.

  2013cited by this paper
• Siderophore-mediated cargo delivery to the cytoplasm of Escherichia coli and Pseudomonas aeruginosa: syntheses of monofunctionalized enterobactin scaffolds and evaluation of enterobactin-cargo conjugate uptake.

  2012cited by this paper
• Discovery of an iron-regulated citrate synthase in Staphylococcus aureus.

  2012cited by this paper
• Chemical syntheses and in vitro antibacterial activity of two desferrioxamine B-ciprofloxacin conjugates with potential esterase and phosphatase triggered drug release linkers.

  2012cited by this paper
• Syntheses of Siderophore-Drug Conjugates Using a Convergent Thiol-Maleimide System.

  2012influential reference
• A Global Investigation of the Bacillus subtilis Iron-Sparing Response Identifies Major Changes in Metabolism

  2012cited by this paper
• Mutation of L-2,3-diaminopropionic acid synthase genes blocks staphyloferrin B synthesis in Staphylococcus aureus

  2011cited by this paper
• In Vitro and In Vivo Properties of BAL30376, a β-Lactam and Dual β-Lactamase Inhibitor Combination with Enhanced Activity against Gram-Negative Bacilli That Express Multiple β-Lactamases

  2011cited by this paper
• Structural basis for effectiveness of siderophore-conjugated monocarbams against clinically relevant strains of Pseudomonas aeruginosa

  2010cited by this paper
• 68Ga-Siderophores for PET Imaging of Invasive Pulmonary Aspergillosis: Proof of Principle

  2010cited by this paper
• In Vitro Properties of BAL30072, a Novel Siderophore Sulfactam with Activity against Multiresistant Gram-Negative Bacilli

  2010cited by this paper
• Catalysis at the Intersection of Biology, Chemistry, and Medicine

  2010cited by this paper
• Identification and characterization of the Staphylococcus aureus gene cluster coding for staphyloferrin A.

  2009cited by this paper
• Molecular characterization of staphyloferrin B biosynthesis in Staphylococcus aureus

  2009cited by this paper
• Synthesis of citrate-ciprofloxacin conjugates.

  2009cited by this paper
• From Siderophores and Self‐Assembly to Luminescent Sensors: The Binding of Molybdenum by Catecholamides

  2009cited by this paper
• Three siderophores from one bacterial enzymatic assembly line.

  2009cited by this paper
• A latent oxazoline electrophile for N-O-C bond formation in pseudomonine biosynthesis.

  2008cited by this paper
• Directed evolution of aryl carrier proteins in the enterobactin synthetase

  2007cited by this paper
• Assembly-line enzymology for polyketide and nonribosomal Peptide antibiotics: logic, machinery, and mechanisms.

  2006cited by this paper
• Albomycin Uptake via a Ferric Hydroxamate Transport System of Streptococcus pneumoniae R6

  2006cited by this paper
• Staphylococcus aureus Redirects Central Metabolism to Increase Iron Availability

  2006cited by this paper
• In vitro characterization of salmochelin and enterobactin trilactone hydrolases IroD, IroE, and Fes.

  2005cited by this paper
• Identification of a cluster of genes that directs desferrioxamine biosynthesis in Streptomyces coelicolor M145.

  2004cited by this paper
• Identification and transcriptional organization of a gene cluster involved in biosynthesis and transport of acinetobactin, a siderophore produced by Acinetobacter baumannii ATCC 19606T.

  2004cited by this paper
• Role of Siderophore Biosynthesis in Virulence of Staphylococcus aureus: Identification and Characterization of Genes Involved in Production of a Siderophore

  2004cited by this paper
• Iron oxide dissolution and solubility in the presence of siderophores

  2004cited by this paper
• Enterobactin: An archetype for microbial iron transport

  2003cited by this paper
• Epimerization of an L-cysteinyl to a D-cysteinyl residue during thiazoline ring formation in siderophore chain elongation by pyochelin synthetase from Pseudomonas aeruginosa.

  2003cited by this paper
• Genetics and Assembly Line Enzymology of Siderophore Biosynthesis in Bacteria

  2002cited by this paper
• In Vivo Synthesis of the Periplasmic Domain of TonB Inhibits Transport through the FecA and FhuA Iron Siderophore Transporters of Escherichia coli

  2001cited by this paper
• Essential PchG-Dependent Reduction in Pyochelin Biosynthesis of Pseudomonas aeruginosa

  2001cited by this paper
• The plug domain of FepA, a TonB-dependent transport protein from Escherichia coli, binds its siderophore in the absence of the transmembrane barrel domain

  2001cited by this paper
• In vitro reconstitution of the Pseudomonas aeruginosa nonribosomal peptide synthesis of pyochelin: characterization of backbone tailoring thiazoline reductase and N-methyltransferase activities.

  2001cited by this paper
• Vancomycin resistance in enterococci: reprogramming of the D-ala-D-Ala ligases in bacterial peptidoglycan biosynthesis.

  2000cited by this paper
• A potent seryl tRNA synthetase inhibitor SB-217452 isolated from a Streptomyces species.

  2000cited by this paper
• Staphyloferrin B, a Citrate Siderophore of Ralstonia eutropha

  1999cited by this paper
• Crystal structure of the outer membrane active transporter FepA from Escherichia coli

  1999cited by this paper
• Enterobactin biosynthesis in Escherichia coli: isochorismate lyase (EntB) is a bifunctional enzyme that is phosphopantetheinylated by EntD and then acylated by EntE using ATP and 2,3-dihydroxybenzoate.

  1997cited by this paper
• Regions of Escherichia coli TonB and FepA proteins essential for in vivo physical interactions

  1997cited by this paper
• A new enzyme superfamily - the phosphopantetheinyl transferases.

  1996cited by this paper
• Energy-coupled transport and signal transduction through the gram-negative outer membrane via TonB-ExbB-ExbD-dependent receptor proteins.

  1995cited by this paper
• Isolation and biological characterization of staphyloferrin B, a compound with siderophore activity from staphylococci.

  1994cited by this paper
• Coordination chemistry of microbial iron transport. 49. The vanadium(IV) enterobactin complex: structural, spectroscopic, and electrochemical characterization

  1993cited by this paper
• Overexpression and purification of ferric enterobactin esterase from Escherichia coli. Demonstration of enzymatic hydrolysis of enterobactin and its iron complex.

  1992cited by this paper
• The First Structural Characterization of a Metal–Enterobactin Complex: [V(enterobactin)]2−

  1992cited by this paper
• In vivo inhibition of TonB-dependent processes by a TonB box consensus pentapeptide

  1992cited by this paper
• Genetic analysis of the enterobactin gene cluster in Shigella flexneri

  1991cited by this paper
• In vitro activity and beta-lactamase stability of GR69153, a new long-acting cephalosporin

  1991cited by this paper
• Overexpression, purification, and characterization of isochorismate synthase (EntC), the first enzyme involved in the biosynthesis of enterobactin from chorismate.

  1990cited by this paper
• Staphyloferrin A: a structurally new siderophore from staphylococci.

  1990cited by this paper
• Subcloning of the enterobactin biosynthetic gene entB: expression, purification, characterization, and substrate specificity of isochorismatase.

  1990cited by this paper
• EntG activity of Escherichia coli enterobactin synthetase

  1990cited by this paper
• Mode of action of GR69153, a novel catechol-substituted cephalosporin, and its interaction with the tonB-dependent iron transport system

  1990cited by this paper
• Intracellular activation of albomycin in Escherichia coli and Salmonella typhimurium

  1983cited by this paper
• Constitution of the Deferriform of the Albomycins δ1, δ2 and ε

  1982cited by this paper
• Suicide substrates: mechanism-based enzyme inactivators

  1982cited by this paper
• Pyochelin: novel structure of an iron-chelating growth promoter for Pseudomonas aeruginosa.

  1981cited by this paper
• Ferric ion sequestering agents. 2. Kinetics and mechanism of iron removal from transferrin by enterobactin and synthetic tricatechols

  1979cited by this paper
• Uptake and conversion of the antibiotic albomycin by Escherichia coli K-12.

  1979cited by this paper
• Desferoxamine mesylate (Desferal): a contrast-enhancing agent for gallium-37 imaging.

  1979cited by this paper

• The hiuABC operon mediates xenosiderophore utilization in Caulobacter crescentus

  2026cites this paper
• Physico-Chemical Properties of bis-2-(2-Hydroxyphenyl)-thiazole-carboxamide (BHPTC) Chelators.

  2026cites this paper
• Bacterial Siderophore Production in Metal-Rich Environments: Underexplored Sources of Siderophores and Insights into Bioremediation.

  2026cites this paper
• From antibiotic to peptide siderophore conjugates as modular strategies against multidrug-resistant bacteria

  2026cites this paper
• Disulfiram induces redox imbalance and perturbations in central glucose catabolism and metal homeostasis to inhibit the growth of Staphylococcus aureus

  2025influential citation
• Recent advances in metallophore research uncover functions in quorum sensing, antimicrobial activity, and lanthanide acquisition.

  2025cites this paper
• Public goods-mediated bacterial interplay in aquatic ecosystems.

  2025cites this paper
• Dual inhibition of cell wall biosynthesis and iron scavenging: Novel strategy against MDR Klebsiella pneumoniae.

  2025cites this paper
• Metals in Motion: Understanding Labile Metal Pools in Bacteria

  2025cites this paper
• Cefiderocol as an alternative antibiotic therapy for treating severe Stenotrophomonas maltophilia infections.

  2025cites this paper
• Photodecarboxylation of the Siderophore Aerobactin with the Lewis Acidic Metal Ions Fe(III), Ga(III), and Ti(IV)

  2025cites this paper
• Rumen Fluid Metabolomics and Microbiome Profiling of Dairy Cows Fed Combinations of Prebiotics, Essential Oil Blend, and Onion Peel Using the RUSITEC System

  2025cites this paper
• The hiuABC Operon Mediates Xenosiderophore Utilization in Caulobacter crescentus

  2025cites this paper
• Modular Synthesis of Desferrioxamine B and Its Methotrexate Conjugate as a Selective Trojan Horse Antibiotic That Targets Streptococcus pneumoniae.

  2025cites this paper
• Targeting Siderophore Biosynthesis to Thwart Microbial Growth

  2025cites this paper
• Genome-guided discovery of coublibactins from Nocardia coubleae and their gallium complexes with potent antileukemic activity.

  2025cites this paper