Siderophore Biosynthesis Inhibitors: A Novel Strategy Against Microbial Virulence and Resistance 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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Metals
Metals
OverviewHeavy metals play a significant and multifaceted role in the pathogenicity of microbial species. Their involvement can be viewed from two primary perspectives: the toxicity of heavy metals to microbes and the exploitation of heavy metals by microbial pathogens to establish infections and evade the host immune response. Understanding these aspects is critical for both […]
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Microbes
Microbes
Microbes, short for microorganisms, are tiny living organisms that are ubiquitous in the environment, including on and inside the human body. They play a crucial role in human health and disease, functioning within complex ecosystems in various parts of the body, such as the skin, mouth, gut, and respiratory tract. The human microbiome, which is […]
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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 comprehensive review explores the inhibition of siderophore biosynthesis as a promising antimicrobial strategy, particularly in the context of increasing resistance to conventional antibiotics. Siderophores—small, high-affinity iron-chelating compounds secreted by microbes—are essential for pathogenic survival under iron-limited conditions. The review delineates three main siderophore biosynthetic pathways: nonribosomal peptide synthetase (NRPS)-dependent, polyketide synthase (PKS)-based, and NRPS-independent (NIS) systems. It presents siderophore production as a key virulence factor and offers an extensive analysis of enzyme targets, including NRPS adenylation domains, phosphopantetheinyl transferases (PPTases), salicylate synthases, and siderophore transport systems. Recent advances in rational drug design, nanoparticle delivery systems, and CRISPR-based genetic manipulation are also explored as innovative tools to suppress microbial iron acquisition. This review consolidates a fragmented literature base, presenting a unified therapeutic framework for antimicrobial intervention by targeting microbial iron uptake pathways.
Who was reviewed?
The review synthesizes data from a broad range of microbial taxa, including bacteria such as Mycobacterium tuberculosis, Staphylococcus aureus, Pseudomonas aeruginosa, Bacillus anthracis, and fungi such as Aspergillus fumigatus. These organisms span both Gram-negative and Gram-positive pathogens and include non-tuberculous mycobacteria (NTMs). Emphasis is placed on their shared reliance on siderophore systems for iron acquisition and pathogenesis. The microbial targets are selected based on their clinical relevance in antimicrobial resistance, virulence, and capacity to biosynthesize diverse siderophore classes.
Most important findings
The review identifies and characterizes a wide array of inhibitors and intervention strategies that target siderophore biosynthesis, grouped by enzyme class and mechanism of action. The review also highlights: Use of CRISPR-Cas9 to disrupt siderophore biosynthetic genes. Nanoparticles (e.g., zinc oxide, gold) as delivery tools and direct inhibitors of siderophore-mediated virulence. The distinction between bactericidal and antivirulence approaches, where the latter may reduce selective resistance pressures. Below is a condensed summary in table format:
| Enzyme Target | Inhibitor Class | Example Compound(s) | IC₅₀ Range | Target Organism(s) |
|---|---|---|---|---|
| PPTase (NRPS) | Allosteric Inhibitors | ML267 | 0.29 µM | S. aureus, B. subtilis |
| PPTase (PptT in M. tb) | Amidino-urea analogues | Compounds 1–10 | 0.018–8.29 µM | M. tuberculosis |
| Adenylation domains (NRPS) | Salicyl-AMS & derivatives | Salicyl-AMS, Compound 15 | 10.7–12 nM | M. tuberculosis, Y. pestis |
| Salicylate Synthase (MbtI) | Furanic inhibitors | Compounds 19–22 | 2.6–12.1 µM | M. tuberculosis, M. abscessus |
| DHB Adenylation Domains | Bisubstrate analogs | DHB-AMS, Compound 23 | 4.5–85 nM | E. coli, B. subtilis |
| NIS Synthetase | Natural products | Baulamycin A & B | 4.8–200 µM | S. aureus, B. anthracis |
| SidA (fungal hydroxylase) | Natural product (noncompetitive) | Celastrol | 11 µM | A. fumigatus |
| FAAL/FACL (PKS-like enzymes) | Fatty acyl-AMS analogues | Hexanoyl-AMS, etc. | NA | M. tuberculosis |
Key implications
Targeting siderophore biosynthesis presents a viable strategy for next-generation antimicrobial therapies, especially against multidrug-resistant organisms. Inhibitors that act on PPTases, adenylation domains, and salicylate synthases can impair iron acquisition and attenuate virulence without necessarily killing the pathogen, potentially reducing evolutionary pressures for resistance. The specificity of some inhibitors, such as ML267 and Salicyl-AMS analogues, enables narrow-spectrum approaches, while nanoparticle systems offer targeted delivery and immune synergy. The integration of genetic tools such as CRISPR enables mechanistic dissection of iron acquisition and opens avenues for strain engineering in microbial therapeutics. However, challenges remain in achieving selectivity, in vivo stability, and delivery to biofilm-embedded pathogens. Further exploration of NIS and fungal-specific pathways is warranted to diversify the antimicrobial toolkit.
Citation
Rocha BM, Pinto E, Sousa E, Resende DISP. Targeting siderophore biosynthesis to thwart microbial growth. Int J Mol Sci. 2025;26(8):3611. doi:10.3390/ijms26083611
Siderophores
Siderophores are microbial iron-chelating molecules that enable pathogens to overcome host iron restriction, shape microbiome ecology, and serve as therapeutic targets.
Siderophores
Siderophores are microbial iron-chelating molecules that enable pathogens to overcome host iron restriction, shape microbiome ecology, and serve as therapeutic targets.
Staphylococcus aureus (S. Aureus)
Staphylococcus aureus is a versatile skin and mucosal commensal that can transition into a highly virulent pathobiont. Known for its immune-evasive strategies, toxin production, and antibiotic resistance, it plays a significant role in chronic infections and microbiome imbalance.
Gram-Negative Bacteria
Gram-negative bacteria are resilient pathogens with antibiotic resistance, causing infections like UTIs, sepsis, and pneumonia.
Siderophores
Siderophores are microbial iron-chelating molecules that enable pathogens to overcome host iron restriction, shape microbiome ecology, and serve as therapeutic targets.