Pathogen Metal Acquisition Systems

ABC Transporters (ATP-Binding Cassette)#

The highest-affinity metal import systems in bacteria. Consist of a periplasmic/surface-associated binding protein, membrane permease, and cytoplasmic ATPase.

Nickel-specific. NikABCDE (E. coli): The prototypical bacterial nickel importer. NikA is the periplasmic binding protein; NikB/C form the transmembrane channel; NikD/E provide the ATPase.

High affinity, capable of scavenging nickel at very low concentrations.^{[1]Role of Nickel in Microbial PathogenesisRobert J. Maier, Stéphane L. Benoit · 2019Open reference 1 ↓}

NiuBDE (H. pylori): ABC-type nickel transporter that operates at acidic pH—essential for the gastric niche where low pH is constant.^{[1]Role of Nickel in Microbial PathogenesisRobert J. Maier, Stéphane L. Benoit · 2019Open reference 1 ↓}

UreMQO (S. salivarius): The only characterized nickel transporter in Streptococci. Part of the nickel (Ni)-dependent Urease operon.^{[2]Metal Homeostasis in Pathogenic StreptococciAkbari MS, Doran KS, Burcham LR · 2022Open reference 2 ↓}

Iron-specific. PitABCD (Streptococci): Iron import system. FeoABC: Ferrous iron (iron(II) (Fe2+)) transport; widely distributed across Gram-negative and some Gram-positive pathogens.^{[2]Metal Homeostasis in Pathogenic StreptococciAkbari MS, Doran KS, Burcham LR · 2022Open reference 2 ↓}

PiaA/PiuA (S. pneumoniae): Iron acquisition proteins contributing to virulence in pneumococcal infection.

Siderophore ABC transporters: Import siderophore-iron complexes (e.g., staphyloferrin A/B uptake in S. aureus).^{[3]Metal Ion Acquisition in Staphylococcus aureus: Overcoming Nutritional ImmunityJames E. Cassat, Eric P. Skaar · 2012Open reference 3 ↓}

Zinc-specific. AdcABC/AdcAII (Streptococci): Primary zinc import system. AdcA and AdcAII are two distinct zinc-binding lipoproteins with complementary roles.

Mutants show attenuated colonization across multiple infection models (nasopharynx, tooth, meningitis, skin).^{[2]Metal Homeostasis in Pathogenic StreptococciAkbari MS, Doran KS, Burcham LR · 2022Open reference 2 ↓}

Lmb (S. agalactiae): Laminin-binding protein that also functions as zinc-binding lipoprotein for import.

Manganese-specific. MntABC/SloABC (Streptococci, Staphylococci): High-affinity manganese (Mn) import critical for superoxide dismutase activity and Oxidative Stress defense.^{[3]Metal Ion Acquisition in Staphylococcus aureus: Overcoming Nutritional ImmunityJames E. Cassat, Eric P. Skaar · 2012Open reference 3 ↓[2]Metal Homeostasis in Pathogenic StreptococciAkbari MS, Doran KS, Burcham LR · 2022Open reference 2 ↓}

Metallophore-metal ABC transporters. CntABCDF (S. aureus): Imports staphylopine-metal complexes (nickel, zinc (Zn), copper (Cu), cobalt (Co)) after the metallophore captures metals extracellularly.^{[1]Role of Nickel in Microbial PathogenesisRobert J. Maier, Stéphane L. Benoit · 2019Open reference 1 ↓}

NiCoT Secondary Transporters#

Single-component, secondary (proton motive force-driven) transporters specific for nickel and/or cobalt.

NixA (H. pylori): The best-characterized NiCoT. A high-affinity nickel (Ni)-only transporter. NixA works alongside the NiuBDE ABC system, providing redundant nickel import—evidence of how critical nickel acquisition is for H. pylori.^{[1]Role of Nickel in Microbial PathogenesisRobert J. Maier, Stéphane L. Benoit · 2019Open reference 1 ↓}

NixA homologs: Found in other nickel-dependent pathogens. Also characterized in engineered probiotics as a target for metal-sequestering therapy.^{[4]Potential Application of Living Microorganisms in the Detoxification of Heavy MetalsRunqiu Chen, Huaijun Tu, Tingtao Chen · 2022Open reference 4 ↓}

MntH (NRAMP Family)#

Secondary manganese(II) (Mn2+) transporters homologous to host NRAMP1/SLC11A1. Found in Streptococci (S. pyogenes, S. pneumoniae) and other pathogens.^{[2]Metal Homeostasis in Pathogenic StreptococciAkbari MS, Doran KS, Burcham LR · 2022Open reference 2 ↓}

The evolutionary irony: the same NRAMP protein family is used by hosts (NRAMP1 to export metals from phagolysosomes, starving engulfed pathogens) and by pathogens (MntH to import metals for survival).

ECF (Energy-Coupling Factor) Transporters#

Modular ABC-type systems that can switch substrate specificity by exchanging the substrate-binding component. Nickel ECF transporters identified in some pathogens but less well characterized than NikABCDE or NixA.

TonB-Dependent Outer Membrane Receptors#

In Gram-negative bacteria, large beta-barrel proteins in the outer membrane that use TonB/ExbBD energy transduction to import siderophore-metal complexes and heme. FpvA: Pyoverdine-iron (Fe) receptor in P. aeruginosa.^{[5]Presence of the siderophores pyoverdine and pyochelin in the extracellular medium reduces toxic metal accumulation in Pseudomonas aeruginosa and increases bacterial metal toleranceBraud A, Geoffroy V, Hoegy F et al. · 2010Open reference 5 ↓} FptA: Pyochelin-iron receptor in P. aeruginosa.^{[5]Presence of the siderophores pyoverdine and pyochelin in the extracellular medium reduces toxic metal accumulation in Pseudomonas aeruginosa and increases bacterial metal toleranceBraud A, Geoffroy V, Hoegy F et al. · 2010Open reference 5 ↓}

FrpB4: TonB-dependent receptor proposed for nickel transport in some species.

Heme Uptake Systems#

Dedicated machinery to capture host hemoglobin/heme as an iron source.

Isd system (S. aureus): IsdB captures hemoglobin on the cell surface, passes heme through the cell wall (IsdC) and membrane (IsdDEF) into the cytoplasm, where IsdG/IsdI degrade heme to release iron. Heme is the preferred iron source during infection.

S. aureus hemolysins actively lyse red blood cells to liberate hemoglobin.^{[3]Metal Ion Acquisition in Staphylococcus aureus: Overcoming Nutritional ImmunityJames E. Cassat, Eric P. Skaar · 2012Open reference 3 ↓}

Shp/Shr system (Streptococci): Heme relay system; Shr is the surface receptor, Shp the chaperone.^{[2]Metal Homeostasis in Pathogenic StreptococciAkbari MS, Doran KS, Burcham LR · 2022Open reference 2 ↓}

22 kDa and 37 kDa proteins (S. pneumoniae): The first identified hemoglobin/heme-binding membrane proteins in pneumococcus. Both share the KVAFDH motif essential for heme binding. S. pneumoniae can use Hb and heme but NOT transferrin or lactoferrin as iron sources.^{[6]Streptococcus pneumoniae Requires Iron for Its Viability and Expresses Two Membrane Proteins That Bind Haemoglobin and HaemMaria Elena Romero-Espejel, Marco A. Gonzalez-Lopez, Jose de Jesus Olivares-Trejo · 2013Open reference 6 ↓}

Nickel Storage#

Best characterized in Helicobacter pylori. Hpn: Extraordinary small His-rich protein—47% of residues are Histidine. Forms 20-mers, each monomer binding 5 nickel (Ni)(II) ions.

Present in all gastric Helicobacter species.

Functions as the primary nickel reservoir, buffering against fluctuations in nickel availability.^{[1]Role of Nickel in Microbial PathogenesisRobert J. Maier, Stéphane L. Benoit · 2019Open reference 1 ↓}

HpnI (Hpn-like): 25% histidine, binds 2 nickel(II) per monomer. Restricted to H. pylori and H. acinonychis. Competes with Hpn for nickel under low-nickel conditions.

Recent work reveals Hpn/HpnI interact with a much wider array of proteins than expected, including urease/Hydrogenase maturation enzymes (delivering nickel to these virulence factors), AmiE (aliphatic amidase), and PepA (aminopeptidase). They function as central nickel distribution hubs in the cell.^{[1]Role of Nickel in Microbial PathogenesisRobert J. Maier, Stéphane L. Benoit · 2019Open reference 1 ↓}

HspA: A GroES (chaperonin) homolog with a unique His-rich C-terminus for nickel binding. Dual function: protein folding chaperone and nickel storage. Candidate for anti-H. pylori vaccine.^{[1]Role of Nickel in Microbial PathogenesisRobert J. Maier, Stéphane L. Benoit · 2019Open reference 1 ↓}

Iron Storage#

Ferritins: Ubiquitous iron storage cages (24 subunits, up to 4,500 iron (Fe) atoms per cage). Found across bacterial phyla. Bacterioferritins: Bacterial-specific ferritin homologs with a heme cofactor.

Protect against iron-mediated Fenton chemistry by sequestering free iron.

Dps (DNA-binding protein from starved cells): Miniferritin (12 subunits); protects DNA from oxidative damage by sequestering iron(II) and preventing Fenton reaction.

Zinc/Other Metal Storage#

Pht proteins (Streptococci): Polyhistidine triad proteins that bind zinc and serve as extracellular zinc reservoirs/trafficking proteins.^{[2]Metal Homeostasis in Pathogenic StreptococciAkbari MS, Doran KS, Burcham LR · 2022Open reference 2 ↓} Metallothionein-like proteins: Small cysteine-rich proteins that bind multiple metals; found in some pathogenic bacteria.

NikR (Nickel-Responsive)#

Ni2+-sensing transcriptional regulator. In H. pylori, NikR both activates and represses genes depending on nickel levels. At high nickel (Ni): activates urease (ureA) expression, nickel storage (hpn), and nickel efflux (cznABC).

At low nickel: depresses import systems.

NikR is essential for balancing nickel acquisition with toxicity avoidance.^{[1]Role of Nickel in Microbial PathogenesisRobert J. Maier, Stéphane L. Benoit · 2019Open reference 1 ↓}

Fur (Ferric Uptake Regulator)#

The master Fe2+-responsive regulator in most bacteria. When iron is sufficient, iron (Fe)-Fur represses siderophore biosynthesis and iron import genes. When iron is scarce, derepression allows maximal iron acquisition.

Also regulates virulence factors, acid resistance, and oxidative stress defense. Fur homologs control manganese (Mur) and zinc (Zur) in some species.

Zur (Zinc Uptake Regulator)#

Zn2+-responsive repressor. Represses zinc import (adcABC) when zinc is sufficient. In Streptococci, Zur also influences Pht protein expression and zinc trafficking.^{[2]Metal Homeostasis in Pathogenic StreptococciAkbari MS, Doran KS, Burcham LR · 2022Open reference 2 ↓}

MntR (Manganese Transport Regulator)#

Mn2+-responsive activator/repressor. Coordinates manganese import with export to maintain homeostasis.

In S. pneumoniae, MntR and the manganese-sensing SczA regulate the balance between manganese (Mn) import (MntABC) and manganese efflux (MntE).^{[2]Metal Homeostasis in Pathogenic StreptococciAkbari MS, Doran KS, Burcham LR · 2022Open reference 2 ↓}

CadR/MerR-Type Regulators#

CadR (A. baumannii): Highly attuned cadmium sensor; activates czcE expression ~480-fold upon cadmium (Cd) exposure.^{[7]The Molecular Basis of Acinetobacter baumannii Cadmium Toxicity and ResistanceAlquethamy SF, Adams FG, Maharjan R et al. · 2021Open reference 7 ↓} CopY (Streptococci): copper (Cu)-responsive repressor controlling copper efflux via CopA.^{[2]Metal Homeostasis in Pathogenic StreptococciAkbari MS, Doran KS, Burcham LR · 2022Open reference 2 ↓}

CDF (Cation Diffusion Facilitator) Family#

CzcD (Streptococci): Zinc exporter.^{[2]Metal Homeostasis in Pathogenic StreptococciAkbari MS, Doran KS, Burcham LR · 2022Open reference 2 ↓}

CzcE (A. baumannii): Primary cadmium exporter; translocates cadmium (Cd) from cytoplasm to periplasm. Mutants are 30-fold more sensitive to cadmium.^{[7]The Molecular Basis of Acinetobacter baumannii Cadmium Toxicity and ResistanceAlquethamy SF, Adams FG, Maharjan R et al. · 2021Open reference 7 ↓}

MntE (Streptococci): Manganese exporter preventing manganese (Mn) toxicity.^{[2]Metal Homeostasis in Pathogenic StreptococciAkbari MS, Doran KS, Burcham LR · 2022Open reference 2 ↓}

HME (Heavy Metal Efflux) RND Systems#

CzcCBA (A. baumannii, H. pylori): Three-component system spanning inner membrane, periplasm, and outer membrane. Exports cadmium (Cd), zinc (Zn), and nickel (Ni) from periplasm to extracellular space, completing a two-step translocation (CDF: cytoplasm-->periplasm, HME: periplasm-->exterior).^{[7]The Molecular Basis of Acinetobacter baumannii Cadmium Toxicity and ResistanceAlquethamy SF, Adams FG, Maharjan R et al. · 2021Open reference 7 ↓}

CznABC (H. pylori): Cadmium, zinc, and nickel efflux. Critical for surviving in the metal-variable gastric environment.^{[1]Role of Nickel in Microbial PathogenesisRobert J. Maier, Stéphane L. Benoit · 2019Open reference 1 ↓}

P-Type ATPases#

CopA (Streptococci): copper (Cu)-exporting P-type ATPase; essential for surviving host copper toxicity in phagosomes.^{[2]Metal Homeostasis in Pathogenic StreptococciAkbari MS, Doran KS, Burcham LR · 2022Open reference 2 ↓} PmtA (S. pyogenes, S. suis): Iron-exporting ATPase.^{[2]Metal Homeostasis in Pathogenic StreptococciAkbari MS, Doran KS, Burcham LR · 2022Open reference 2 ↓} ZccE (S. mutans): Unique zinc-exporting P-type ATPase.^{[2]Metal Homeostasis in Pathogenic StreptococciAkbari MS, Doran KS, Burcham LR · 2022Open reference 2 ↓}

P-type ATPases are also upregulated in Enterococcus under cadmium stress for cadmium (Cd) export.^{[8]Cadmium stress triggers significant metabolic reprogramming in Enterococcus faecium CX 2-6Cheng X, Yang B, Zheng J et al. · 2021Open reference 8 ↓}

Metal Efflux as Counter to Host Toxicity#

The host deliberately floods phagolysosomes with copper and zinc to kill engulfed bacteria. Pathogen copper/zinc efflux systems (CopA, CzcD, CznABC) are therefore virulence factors—enabling survival of the host's metal intoxication strategy.^{[2]Metal Homeostasis in Pathogenic StreptococciAkbari MS, Doran KS, Burcham LR · 2022Open reference 2 ↓[3]Metal Ion Acquisition in Staphylococcus aureus: Overcoming Nutritional ImmunityJames E. Cassat, Eric P. Skaar · 2012Open reference 3 ↓}

PMI1518 (P. mirabilis): Nickel efflux system essential for catheter-associated UTI, preventing nickel toxicity in the urinary niche.^{[1]Role of Nickel in Microbial PathogenesisRobert J. Maier, Stéphane L. Benoit · 2019Open reference 1 ↓}