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Cited by 21Hemoglobin structure and functionBacterial Genetics and BiotechnologyEscherichia coli research studies

The DOI matches its Crossref record; 369 of the 369 references it cites were found in a registry or an index.

Heme in Bacterial Pathogenesis and as an Antimicrobial Target

Open access
Chen, Pei-Yi, Skaar, Eric P.·2025·Chemical Reviews
DOI 10.1021/acs.chemrev.5c00528PMC PMC12670364
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Abstract

Heme is an essential molecule required for critical biochemical processes in most vertebrates and bacteria. During infections, vertebrate hosts sequester heme away from invading pathogens, a process known as nutritional immunity, driving bacteria to evolve diverse mechanisms to evade this immunity and cause diseases. This review explores the functions of heme at the host-pathogen interface. We discuss the multifaceted roles of heme in bacterial pathogenesis and the potential for heme-targeting antimicrobial therapies. Beyond serving as a source of iron in the host environment, where iron bioavailability is limited, heme contributes to the structural stability and enzymatic functions of hemoproteins. We examine the regulatory mechanisms governing bacterial heme homeostasis in the host environment including sensing, detoxification, acquisition, utilization, and degradation pathways. Understanding how heme influences bacterial survival and virulence can lead to the development of novel therapeutic strategies that target the various essential and conserved mechanisms of heme homeostasis in bacterial pathogens. Given the rising challenge of antibiotic resistance, heme-based therapeutic interventions are promising strategies for the treatment of bacterial infections.

Overview

CoChat Summary

TL;DR

This review synthesizes how heme drives bacterial pathogenesis at the host–pathogen interface and how conserved heme homeostasis pathways—sensing, detoxification, acquisition, utilization, and degradation—can be targeted by antimicrobials. It highlights heme mimics, photodynamic therapy, and inhibitors of heme biosynthesis, uptake, and degradation as promising strategies against antibiotic-resistant pathogens.

Key findings

  • Host nutritional immunity sequesters heme and iron; vertebrates store ~70% of available iron as heme or heme-bound proteins, and labile iron in serum and interstitial fluids is roughly 10–30 μM, while heme-requiring bacterial pathogens generally require 0.1–10 μM heme for optimal growth.
  • Bacterial pathogens use diverse heme acquisition systems (e.g., *S. aureus* Isd, *P. aeruginosa* Has/Phu/Hxu) and degradation enzymes (HO-1 family, IsdG family, MhuD, anaerobic degraders) to obtain iron, populate hemoproteins, and detoxify heme; these systems contribute to virulence in animal infection models.
  • Heme and its catabolites are immunomodulatory: free heme is a DAMP recognized by TLR2/TLR4; bilirubin is antioxidant at low concentration (7 ng/mg protein) but pro-oxidant at high concentration (25 ng/mg protein); *P. aeruginosa* HemO releases BVIXδ and BVIXβ in a 70:30 ratio, and these may act as signaling molecules.
  • Heme-based therapeutics include non-iron metalloporphyrins (Ga-, Co-, Cu-, Zn-, Mn-PPIX), photodynamic therapy, and inhibitors of heme biosynthesis/uptake/degradation; e.g., Ga-PPIX inhibits growth of *S. aureus*, *P. aeruginosa*, *A. baumannii*, *K. pneumoniae*, and *M. tuberculosis* in vitro or in vivo, though resistance/tolerance and host toxicity concerns remain.

Methods

  • Narrative review; no primary experiments. It synthesizes literature on mammalian heme metabolism, bacterial hemoproteins, heme sensing/detoxification, acquisition, degradation, and heme-targeting therapeutics.
  • Discusses specific bacterial systems and animal/in vitro studies from cited literature; no systematic search or meta-analysis is described.
  • Main analysis is conceptual synthesis and figure-based pathway models.

Limitations

  • The paper does not state limitations.
  • Evident from the text: it is a narrative review without systematic search criteria, quantitative synthesis, or primary data, so selection and interpretation may be subject to author bias.
  • Evident: therapeutic strategies are largely supported by preclinical in vitro/animal studies; the review notes concerns about host toxicity and bacterial resistance/tolerance to metal-based drugs, but does not provide clinical trial evidence.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1021/acs.chemrev.5c00528

Cites

369 of 369 references verified0 citation errors · 0 not checkable

Statistics

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Figures

1 Host heme metabolism and activation of the innate immune response. Upon hemolysis, host erythrocytes release heme and hemoglobin, which can readily generate reactive oxygen species. Host proteins hemopexin and haptoglobin scavenge labile heme and hemoglobin for recycling and keeping them away from invading pathogens. Heme is recognized by Toll-like receptors (TLRs) 2 and 4 as a damage associated molecular pattern, which activates the NF-κB pathway to induce the production of interferon regulatory factors (IRFs). Heme also downregulates the production of TLR2 and TLR4. The reactive oxygen species generated by the cytoplasmic heme activate STING, which also activates NF-κB downstream. To limit oxidative damage, host heme oxygenases degrade heme to biliverdin IXα (BVIXα), iron, and carbon monoxide (CO). Transferrin binds to free iron. Biliverdin is then conjugated to bilirubin by biliverdin reductase, which is shuttled to the liver for downstream metabolism. Biliverdin and bilirubin are both antioxidants.
1 Host heme metabolism and activation of the innate immune response. Upon hemolysis, host erythrocytes release heme and hemoglobin, which can readily generate reactive oxygen species. Host proteins hemopexin and haptoglobin scavenge labile heme and hemoglobin for recycling and keeping them away from invading pathogens. Heme is recognized by Toll-like receptors (TLRs) 2 and 4 as a damage associated molecular pattern, which activates the NF-κB pathway to induce the production of interferon regulatory factors (IRFs). Heme also downregulates the production of TLR2 and TLR4. The reactive oxygen species generated by the cytoplasmic heme activate STING, which also activates NF-κB downstream. To limit oxidative damage, host heme oxygenases degrade heme to biliverdin IXα (BVIXα), iron, and carbon monoxide (CO). Transferrin binds to free iron. Biliverdin is then conjugated to bilirubin by biliverdin reductase, which is shuttled to the liver for downstream metabolism. Biliverdin and bilirubin are both antioxidants.CC BY · PubMed Central
2 Heme sensing and detoxification systems. (A) Staphylococcus aureus heme-sensing two-component element HssS, upon binding heme, phosphorelays to HssR. Phosphorylated HssR dimerizes and translocates to the promoter regions of the hrtAB and hssRS operons. ABC membrane permease complex HrtAB then effluxes excess heme out of the cytoplasm. (B) Apo Lactococcus lactis HrtR binds to the promoter region of the hrtRBA operon to repress expression. Heme binding induces a conformational change to allow holo-HrtR to dissociate from the hrtRBA promoter. (C) Streptococcus agalactiae MarR-type heme-sensing regulator PefR derepresses the pefAB and pefRCD operons when it binds heme. PefCD is an ABC membrane PPIX efflux pump. PefAB is a MFS transporter. (D) Clostridioides difficile heme-sensing regulator HatR derepresses hatRT when bound to heme. HatT is an MFS transporter. HsmR binds heme to activate expression of hsmRA. HsmA is a membrane-bound heme storage and defends against oxidative stress.
2 Heme sensing and detoxification systems. (A) Staphylococcus aureus heme-sensing two-component element HssS, upon binding heme, phosphorelays to HssR. Phosphorylated HssR dimerizes and translocates to the promoter regions of the hrtAB and hssRS operons. ABC membrane permease complex HrtAB then effluxes excess heme out of the cytoplasm. (B) Apo Lactococcus lactis HrtR binds to the promoter region of the hrtRBA operon to repress expression. Heme binding induces a conformational change to allow holo-HrtR to dissociate from the hrtRBA promoter. (C) Streptococcus agalactiae MarR-type heme-sensing regulator PefR derepresses the pefAB and pefRCD operons when it binds heme. PefCD is an ABC membrane PPIX efflux pump. PefAB is a MFS transporter. (D) Clostridioides difficile heme-sensing regulator HatR derepresses hatRT when bound to heme. HatT is an MFS transporter. HsmR binds heme to activate expression of hsmRA. HsmA is a membrane-bound heme storage and defends against oxidative stress.CC BY · PubMed Central
3 Structural rearrangement of hemoproteins upon ligand binding. Crystal structures of Lactococcus lactis HrtR and Corynebacterium diphtheriae HmuO. (A) The helix–coil–helix structure of α helix 4 on each of the monomers allows apo-HrtR to bind to the target DNA (PDB: 3VOX). (B) Holo-HrtR dimer. Binding of heme ligand in the hydrophobic pocket induces a coil-to-helix conformation change of α helix 4, which pushes the α helix 3 outward, leading to distancing between the DNA-binding residues and the DNA major groove (PDB: 3VP5). (C) Apo-HmuO proximal and distal helices to the heme-binding pocket are in helix–coil–helix conformations (PDB: 4GOH). (D) Holo-HmuO distal and proximal helices take on the coil-to-helix change and form a closed heme pocket (PDB: 1IW1). Red, heme. Yellow and green are HrtR monomers. Orange, hrtRBA promoter DNA. Blue, HmuO. (A) and (B) are adapted from The Journal of Biological Chemistry, 287 (36), Sawai, H. et al. Structural basis for the transcriptional regulation of heme homeostasis in Lactococcus lactis, 30755–30768, Copyright Elsevier (2012). (C) is adapted from The Journal of Biological Chemistry, 288 (48), Unno, M. et al. Structures of the substrate-free and product-bound forms of HmuO, a heme oxygenase from Corynebacterium diphtheriae: X-ray crystallography and molecular dynamics investigation, 34443–34458, Copyright Elsevier (2013). (D) is adapted from The Journal of Biological Chemistry, 279 (12), Hirotsu S. et al. The crystal structures of the ferric and ferrous forms of the heme complex of HmuO, a heme oxygenase of Corynebacterium diphtheriae, 11937–11947, Copyright Elsevier (2004). All distributed under CC-BY license 4.0 (https://creativecommons.org/licenses/by/4.0/). This figure is produced in PyMOL.
3 Structural rearrangement of hemoproteins upon ligand binding. Crystal structures of Lactococcus lactis HrtR and Corynebacterium diphtheriae HmuO. (A) The helix–coil–helix structure of α helix 4 on each of the monomers allows apo-HrtR to bind to the target DNA (PDB: 3VOX). (B) Holo-HrtR dimer. Binding of heme ligand in the hydrophobic pocket induces a coil-to-helix conformation change of α helix 4, which pushes the α helix 3 outward, leading to distancing between the DNA-binding residues and the DNA major groove (PDB: 3VP5). (C) Apo-HmuO proximal and distal helices to the heme-binding pocket are in helix–coil–helix conformations (PDB: 4GOH). (D) Holo-HmuO distal and proximal helices take on the coil-to-helix change and form a closed heme pocket (PDB: 1IW1). Red, heme. Yellow and green are HrtR monomers. Orange, hrtRBA promoter DNA. Blue, HmuO. (A) and (B) are adapted from The Journal of Biological Chemistry, 287 (36), Sawai, H. et al. Structural basis for the transcriptional regulation of heme homeostasis in Lactococcus lactis, 30755–30768, Copyright Elsevier (2012). (C) is adapted from The Journal of Biological Chemistry, 288 (48), Unno, M. et al. Structures of the substrate-free and product-bound forms of HmuO, a heme oxygenase from Corynebacterium diphtheriae: X-ray crystallography and molecular dynamics investigation, 34443–34458, Copyright Elsevier (2013). (D) is adapted from The Journal of Biological Chemistry, 279 (12), Hirotsu S. et al. The crystal structures of the ferric and ferrous forms of the heme complex of HmuO, a heme oxygenase of Corynebacterium diphtheriae, 11937–11947, Copyright Elsevier (2004). All distributed under CC-BY license 4.0 (https://creativecommons.org/licenses/by/4.0/). This figure is produced in PyMOL.CC BY · PubMed Central
4 Heme uptake systems. Receptor-mediated uptake is represented by the iron surface determinant (Isd) system in the Gram-positive pathogen Staphylococcus aureus. Hemophore-mediated, TonB-mediated uptake is represented by the Pseudomonas heme uptake (Phu), the heme assimilation system (Has), and the hemopexin-binding Hxu system in the Gram-negative pathogen Pseudomonas aeruginosa. (A) S. aureus cell-wall-bound receptors IsdA, IsdB, and IsdH recognize heme, hemoglobin, and haptoglobin–hemoglobin complex. Heme is transferred to IsdC then through the ABC membrane permease complex IsdEFFhuC into the cytoplasm. Heme oxygenases IsdG and IsdI degrade heme to staphylobilin, iron, and formaldehyde. (B) P. aeruginosa HasA is a secreted hemoprotein that binds extracellular heme and hemoglobin and transfers them across the outer membrane by the TonB-ExbBD-dependent receptor HasR. HasR relays heme to periplasmic binding protein PhuT, then to the ABC permease complex PhuUV. Cytoplasmic heme is chaperoned by PhuS to heme oxygenases HemO and BphO, breaking heme to iron, carbon monoxide, and biliverdin IX. Outer membrane receptors PhuR and HxuA both transport heme to PhuT. Ligand-bound HasR inactivates the anti-σ HasS to release the σ factor HasI, inducing has operon expression. Heme binding of HxuA similarly triggers HxuR to release σ factor HxuI to recruit RNA polymerase to the hxu operon promoter. PhuS also negatively regulates prrF operon expression.
4 Heme uptake systems. Receptor-mediated uptake is represented by the iron surface determinant (Isd) system in the Gram-positive pathogen Staphylococcus aureus. Hemophore-mediated, TonB-mediated uptake is represented by the Pseudomonas heme uptake (Phu), the heme assimilation system (Has), and the hemopexin-binding Hxu system in the Gram-negative pathogen Pseudomonas aeruginosa. (A) S. aureus cell-wall-bound receptors IsdA, IsdB, and IsdH recognize heme, hemoglobin, and haptoglobin–hemoglobin complex. Heme is transferred to IsdC then through the ABC membrane permease complex IsdEFFhuC into the cytoplasm. Heme oxygenases IsdG and IsdI degrade heme to staphylobilin, iron, and formaldehyde. (B) P. aeruginosa HasA is a secreted hemoprotein that binds extracellular heme and hemoglobin and transfers them across the outer membrane by the TonB-ExbBD-dependent receptor HasR. HasR relays heme to periplasmic binding protein PhuT, then to the ABC permease complex PhuUV. Cytoplasmic heme is chaperoned by PhuS to heme oxygenases HemO and BphO, breaking heme to iron, carbon monoxide, and biliverdin IX. Outer membrane receptors PhuR and HxuA both transport heme to PhuT. Ligand-bound HasR inactivates the anti-σ HasS to release the σ factor HasI, inducing has operon expression. Heme binding of HxuA similarly triggers HxuR to release σ factor HxuI to recruit RNA polymerase to the hxu operon promoter. PhuS also negatively regulates prrF operon expression.CC BY · PubMed Central
5 Heme is metabolized to diverse chromophores by different degradation enzymes. Heme b is catabolized by the canonical HO-1 family of heme oxygenases, IsdG-family heme oxygenases, IsdG-like MhuD heme oxygenase, and anaerobic heme degraders to diverse linear tetrapyrroles. Blue corresponds to meso carbons of heme b. Iron ion and single carbon byproducts, if applicable, are not shown.
5 Heme is metabolized to diverse chromophores by different degradation enzymes. Heme b is catabolized by the canonical HO-1 family of heme oxygenases, IsdG-family heme oxygenases, IsdG-like MhuD heme oxygenase, and anaerobic heme degraders to diverse linear tetrapyrroles. Blue corresponds to meso carbons of heme b. Iron ion and single carbon byproducts, if applicable, are not shown.CC BY · PubMed Central
6 Targeting the heme homeostasis pathways in bacteria. Maintenance of heme homeostasis is crucial for invading pathogens, which makes the machineries involved in this process attractive targets for the development of novel, antimicrobial therapeutics. λν, photon energy, representing blue or green light, 405–480 or 522 nm. Circles with metal ions, metalloporphyrins; Ga, gallium; Cu, copper; Mn, manganese; Zn, zinc; Co, cobalt. PPD, protoporphyrin-dependent pathway; CPD, coproporphyrin-dependent pathway; uro’gen, uroporphyrinogen III; copro’gen, coproporphyrinogen III; ALA, 5-aminolevulinate acid; PPIX, protoporphyrin IX. In blue, drugs targeting heme homeostasis pathways.
6 Targeting the heme homeostasis pathways in bacteria. Maintenance of heme homeostasis is crucial for invading pathogens, which makes the machineries involved in this process attractive targets for the development of novel, antimicrobial therapeutics. λν, photon energy, representing blue or green light, 405–480 or 522 nm. Circles with metal ions, metalloporphyrins; Ga, gallium; Cu, copper; Mn, manganese; Zn, zinc; Co, cobalt. PPD, protoporphyrin-dependent pathway; CPD, coproporphyrin-dependent pathway; uro’gen, uroporphyrinogen III; copro’gen, coproporphyrinogen III; ALA, 5-aminolevulinate acid; PPIX, protoporphyrin IX. In blue, drugs targeting heme homeostasis pathways.CC BY · PubMed Central

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  1. Balla J., 2003, Nephrol. Dial. Transplant. Off. Publ. Eur. Dial. Transpl. Assoc. - Eur. Ren. Assoc., 18, 8
  2. Medlock A. E., 2017, Met. Act. Site Assem., 1, 299
  3. Schobert M., 2002, J. Mol. Microbiol. Biotechnol., 4, 287
  4. 10.1074/jbc.m112.359265 · DOI

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Metadata

Authors
Chen, P.-Y., & Skaar, E. P.
Affiliations
  • Department of Pathology, Microbiology, and Immunology
  • Vanderbilt University (US)
Corresponding author
Skaar, Eric P.
ORCID
Skaar, Eric P.
Venue
Chemical Reviews
Publisher
American Chemical Society (ACS)
Published
2025-11-17
Volume
125
Issue
22
Pages
11120-11144
ISSN
  • 0009-2665 (ISSN-L)
  • 1520-6890
DOI
10.1021/acs.chemrev.5c00528
PMC
PMC12670364
OpenAlex
W4416724571
Semantic Scholar
38381ad4dfa15f9d261f0feb9631641f2eda673c
Cited by
21
References
369
Citations by year
2026: 19 · 2025: 2
FWCI
1.85
Type
journal article
Language
en
Open access
Licence
Locations
  • Chemical Reviews (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Funders
  • Pfizer
  • National Academy of Sciences
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Hemoglobin structure and function
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Bacterial Genetics and Biotechnology
  • Life Sciences › Immunology and Microbiology › Microbiology › Escherichia coli research studies
Keywords
heme, bacterial pathogenesis, nutritional immunity, heme homeostasis, iron acquisition, heme proteins, heme detoxification, heme degradation, host-pathogen interaction, antibiotic resistance, bacterial virulence
MeSH terms
Animals, Anti-Bacterial Agents, Bacteria, Bacterial Infections, Heme, Humans

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