Recent Advances in Siderophore Biosynthesis Pathways: Implications for Microbial Virulence and Therapeutics Original paper
Researched by:
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Karen Pendergrass
ID
Karen Pendergrass
Read MoreKaren Pendergrass is a microbiome researcher specializing in microbiome-targeted interventions (MBTIs). She systematically analyzes scientific literature to identify microbial patterns, develop hypotheses, and validate interventions. As the founder of the Microbiome Signatures Database, she bridges microbiome research with clinical practice. In 2012, based on her own investigative research, she became the first documented case of FMT for Celiac Disease—four years before the first published case study.
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Karen Pendergrass
Read More
Researched by:
-
Karen Pendergrass
ID
Karen Pendergrass
Read More
Microbiome Signatures identifies and validates condition-specific microbiome shifts and interventions to accelerate clinical translation. Our multidisciplinary team supports clinicians, researchers, and innovators in turning microbiome science into actionable medicine.
Karen Pendergrass
What was reviewed?
This review synthesizes recent advances in siderophore biosynthesis pathways, focusing on the enzymatic logic, genetic organization, and structural chemistry that enable bacteria to acquire iron under limiting conditions. It integrates mechanistic insights across non-ribosomal peptide synthetase (NRPS) and NRPS-independent (NIS) systems, links siderophore production to virulence, and highlights tractable enzymatic nodes for inhibitor development. The article also contextualizes how modular enzymes can be reprogrammed or inhibited to modulate pathogen fitness without indiscriminately disrupting commensals, which is directly relevant to microbiome-preserving therapeutics.
Who was reviewed?
Evidence is drawn from model and pathogenic taxa that exemplify distinct siderophore solutions and clinical niches. Gram-negative examples include Escherichia coli enterobactin and the Klebsiella-derived microcin E492 conjugate, as well as Vibrio and Yersinia NRPS systems. Gram-positive and actinomycete exemplars include Mycobacterium tuberculosis mycobactins, Streptomyces coelicolor coelichelin, the thermophile Thermobifida fusca fuscachelins, and Bacillus anthracis petrobactin. Environmental producers such as Pseudomonas fluorescens, Shewanella spp., Vibrio salmonicida, and the plant pathogen Erwinia amylovora expand the spectrum to polymicrobial and host-associated ecosystems.
Most important findings
The review also emphasizes the role of siderophores as major microbial virulence factors and points toward their potential exploitation in the development of narrow-spectrum antibiotics or as tools in microbiome modulation strategies. The article outlines numerous microbiome-relevant insights into siderophore biosynthesis:
| Feature | Details |
|---|---|
| NRPS-dependent innovations | NRPSs display non-linear enzymatic logic, including module skipping and iteration (e.g., coelichelin and fuscachelin), challenging the classic collinearity rule. Novel tailoring enzymes (e.g., MceC/D/IJ for microcin E492 modification) and cross-pathway interactions (e.g., MbtH-like proteins in Streptomyces coelicolor) were also elucidated. |
| Antimicrobial targets | Inhibitors of MbtA, such as 5′-O-[(N-salicyl)sulfamoyl]adenosine, show submicromolar inhibition of mycobactin biosynthesis in M. tuberculosis under iron-limited conditions. |
| NRPS-independent discoveries | A new class of oligomerizing–macrocyclizing enzymes (e.g., DesD, BibC, PubC) constructs siderophores like desferrioxamine E, bisucaberin, and putrebactin via freely dissociable intermediates. This mechanism diverges from NRPS-mediated tethered assembly. |
| Hybrid NRPS–NIS pathways | Bacillus anthracis employs a hybrid pathway for petrobactin biosynthesis, with NIS enzymes AsbA and AsbB catalyzing key condensation steps. These enzymes show strict substrate specificity, offering rational drug design opportunities. |
| Thiocarboxylate biosynthesis | The siderophore thioquinolobactin uses a rare thiocarboxylate ligand formed through a sulfur transfer mechanism involving QbsC/D/E. |
Key implications
The elucidation of siderophore biosynthesis offers multiple clinically relevant insights. First, siderophore pathways are attractive antimicrobial targets, particularly for pathogens reliant on NRPS-dependent (e.g., M. tuberculosis) or NIS-dependent (e.g., B. anthracis) systems. The mechanistic understanding of these pathways facilitates rational inhibitor design, with potential for dual-use as microbiome-preserving or conditionally activated drugs. Second, recognition of non-canonical enzymatic logic (e.g., module iteration and skipping) expands our toolkit for biosynthetic reprogramming and synthetic biology applications. Finally, siderophores contribute to microbial fitness, interspecies competition, and host-pathogen interactions—integral concepts in microbiome signature research. Their characterization supports a better understanding of microbial adaptation to host environments, niche colonization, and dysbiosis-associated pathogenesis.
Citation
Barry SM, Challis GL. Recent advances in siderophore biosynthesis.Curr Opin Chem Biol. 2009;13(2):205–215. doi:10.1016/j.cbpa.2009.03.008
Siderophores
Siderophores are microbial iron-chelating molecules that enable pathogens to overcome host iron restriction, shape microbiome ecology, and serve as therapeutic targets.
Escherichia coli (E. coli)
Escherichia coli (E. coli) is a versatile bacterium, from gut commensal to pathogen, linked to chronic conditions like endometriosis.