Iron Acquisition Mechanisms in Mycobacterium Species

Mycobacterium species, notably Mycobacterium tuberculosis, must overcome stringent host-mediated iron limitation to establish infection. These pathogens deploy multiple complementary strategies to scavenge iron from the host environment, including the biosynthesis and secretion of high-affinity siderophores (mycobactin and carboxymycobactin), direct uptake of heme iron, and exploitation of host iron-binding proteins. Siderophore synthesis is initiated by salicylate synthase (MbtI), followed by assembly of iron-chelating mycobactins that are exported via dedicated transporters and reimported upon iron loading. Parallel heme acquisition pathways involve surface-exposed PPE proteins and specific substrate-binding components of inner-membrane transporters. Transcriptional regulators and periplasmic binding proteins coordinate these routes to ensure iron homeostasis under fluctuating environmental conditions. Structural studies of periplasmic loaders reveal discrete binding pockets for heme versus siderophores, indicating specialised import modules. Collectively, these mechanisms underpin the capacity of mycobacteria to persist within iron-restricted niches, contribute to pathogenicity, and represent attractive targets for therapeutic intervention.

Research from Nature Portfolio

Recent studies have delineated convergent pathways for heme uptake in Mycobacterium tuberculosis. One investigation resolved the crystal structure of the DppA substrate-binding protein, revealing a solvent-exposed cleft critical for heme binding and demonstrating that arginine 179 is essential for iron acquisition from both free heme and haemoglobin. This work also established that surface PPE36 and PPE62 proteins coordinate with DppA to mediate cell-surface capture of heme, while albumin can bypass these requirements via an alternative uptake route. In parallel, structure-based virtual screening and pharmacophore modelling endeavours have yielded the first inhibitors of the iron-dependent regulator IdeR, providing proof-of-principle for targeting transcriptional control of iron homeostasis. These compounds inhibit DNA binding by IdeR and suppress mycobacterial growth, highlighting transcriptional regulation as a druggable axis in iron acquisition.

Iron Acquisition Mechanisms in Mycobacterium Species publication trend

The graph below shows the total number of articles in iron acquisition mechanisms in mycobacterium species across all publications each year (not limited to Nature Index journals).

Technical terms

Siderophore: Small, high-affinity iron-chelating molecule secreted by bacteria to solubilise ferric iron.

Salicylate Synthase (SaS/MbtI): Enzyme catalysing the first step in mycobactin biosynthesis from chorismate to salicylate.

Heme: Iron-containing porphyrin ring that serves as the main reservoir of host iron, often bound within haemoglobin.

Substrate-binding Protein: Periplasmic or cell-surface component that captures specific ligands (heme or siderophore) for transport systems.

PPE Proteins: Proline-proline-glutamate surface proteins in mycobacteria implicated in nutrient acquisition including heme uptake.

IdeR: Iron-dependent transcriptional regulator in M. tuberculosis that represses or activates genes involved in iron homeostasis.

References

1. Discovery of a Siderophore Export System Essential for Virulence of Mycobacterium tuberculosis. PLOS Pathogens (2013).
2. PPE Surface Proteins Are Required for Heme Utilization by Mycobacterium tuberculosis. mBio (2017).
3. Heme and hemoglobin utilization by Mycobacterium tuberculosis. Nature Communications (2019).
4. Differentiating the roles of Mycobacterium tuberculosis substrate binding proteins, FecB and FecB2, in iron uptake. PLOS Pathogens (2023).
5. Targeting Siderophore-Mediated Iron Uptake in M. abscessus: A New Strategy to Limit the Virulence of Non-Tuberculous Mycobacteria. Pharmaceutics (2023).
6. The role of transcriptional regulators in metal ion homeostasis of Mycobacterium tuberculosis. Frontiers in Cellular and Infection Microbiology (2024).
7. Virtual Screening, pharmacophore development and structure based similarity search to identify inhibitors against IdeR, a transcription factor of Mycobacterium tuberculosis. Scientific Reports (2017).