Menaquinone biosynthesis potentiates haem toxicity in S taphylococcus aureus
Open accessAbstract
Summary: S taphylococcus aureus is a pathogen that infects multiple anatomical sites leading to a diverse array of diseases. Although vertebrates can restrict the growth of invading pathogens by sequestering iron within haem, S. aureus surmounts this challenge by employing high‐affinity haem uptake systems. However, the presence of excess haem is highly toxic, necessitating tight regulation of haem levels. To overcome haem stress, S. aureus expresses the detoxification system HrtAB. In this work, a transposon screen was performed in the background of a haem‐susceptible, HrtAB‐deficient S. aureus strain to identify the substrate transported by this putative pump and the source of haem toxicity. While a recent report indicates that HrtAB exports haem itself, the haem‐resistant mutants uncovered by the transposon selection enabled us to elucidate the cellular factors contributing to haem toxicity. All mutants identified in this screen inactivated the menaquinone (MK) biosynthesis pathway. Deletion of the final steps of this pathway revealed that quinone molecules localizing to the cell membrane potentiate haem‐associated superoxide production and subsequent oxidative damage. These data suggest a model in which membrane‐associated haem and quinone molecules form a redox cycle that continuously generates semiquinones and reduced haem, both of which react with atmospheric oxygen to produce superoxide.
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Staphylococcus aureus heme toxicity occurs in part due to membrane-associated oxidative damage potentiated by the electron carrier menaquinone.
“S. aureus heme toxicity occurs in part due to membrane-associated oxidative damage, which is potentiated by the electron carrier menaquinone (Wakeman et al., 2012).”
From Iron in infection and immunity (2013) · cites this paper as Wakeman et al., 2012
Heme challenges S. aureus because electron shuttling through heme and quinone molecules in the bacterial cell membrane generates damaging superoxide.
“However heme presents its own challenge for S. aureus as electron shuttling through heme and quinone molecules in the bacterial cell membrane result in the generation of damaging superoxide molecules (Wakeman et al., 2012).”
From The Impact of Dietary Transition Metals on Host-Bacterial Interactions (2018) · cites this paper as Wakeman et al., 2012
Under excess heme in S. aureus, membrane proteins are highly oxidized and superoxide is formed by redox cycling of heme-iron through membrane menaquinone.
“In conditions of excess heme toxicity, membrane proteins are highly oxidized and superoxide is formed by redox cycling of heme-iron through membrane menaquinone [228].”
From Heme Synthesis and Acquisition in Bacterial Pathogens (2016) · cites this paper as [228]
Superoxide production is a separate source of oxidative damage from ferrous iron-mediated ROS and is a major component of heme damage in S. aureus.
“Superoxide production is a separate source of oxidative damage from ferrous iron-mediated ROS and is a major component of heme damage in S. aureus [228].”
From Heme Synthesis and Acquisition in Bacterial Pathogens (2016) · cites this paper as [228]
Heme-mediated ROS is key to heme toxicity, and heme toxicity is primarily localized to the membrane.
“this work also localized heme toxicity primarily to the membrane.”
From Heme Synthesis and Acquisition in Bacterial Pathogens (2016) · cites this paper as [228]
Whole-genome sequencing of a selection of independently isolated menadione-auxotrophs revealed mutations in genes in the menaquinone biosynthetic pathway (aroB and menABDEF).
“Whole-genome sequencing of a selection of each of the independently isolated menadione-auxotrophs (two from TSB only, three from TSB plus H2O2, and three from TSB plus paraquat) revealed mutations in genes in the menaquinone biosynthetic pathway (aroB and menABDEF) (Table 1) (55).”
From Staphylococcus aureus Adapts to Oxidative Stress by Producing H <sub>2</sub> O <sub>2</sub> -Resistant Small-Colony Variants via the SOS Response (2015) · cites this paper as [55]
Wild-type S. aureus exposed to H2O2 increase expression of genes associated with fermentation.
“wild-type S. aureus exposed to H2O2 increase expression of genes associated with fermentation and a Staphylococcus epidermidis mutant lacking a functional TCA cycle displayed elevated resistance to H2O2 killing (54, 55, 84).”
From Staphylococcus aureus Adapts to Oxidative Stress by Producing H <sub>2</sub> O <sub>2</sub> -Resistant Small-Colony Variants via the SOS Response (2015) · cites this paper as [55]
A Staphylococcus epidermidis mutant lacking a functional TCA cycle displayed elevated resistance to H2O2 killing.
“wild-type S. aureus exposed to H2O2 increase expression of genes associated with fermentation and a Staphylococcus epidermidis mutant lacking a functional TCA cycle displayed elevated resistance to H2O2 killing (54, 55, 84).”
From Staphylococcus aureus Adapts to Oxidative Stress by Producing H <sub>2</sub> O <sub>2</sub> -Resistant Small-Colony Variants via the SOS Response (2015) · cites this paper as [55]
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References 70 · Cited by 94
Research works printed but not linked: 4
- Bullen JJ Griffiths E Griffiths JJBaE 1999 Iron and infection Molecular, Physiological and Clinical Aspects 2 New York John Wiley & Sons
- Crichton R Crichton R 2001 Inorganic biochemistry of iron metabolism Molecular Mechanisms to Clinical Consequences 2 West Sussex, England John Wiley & Sons, Ltd
- Gutteridge JM Quinlan GJ Wilkins S 1984 Mitomycin C-induced deoxyribose degradation inhibited by superoxide dismutase. A reaction involving iron, hydroxyl and semiquinone radicals FEBS Letters 167 37 41 6321237
- Jeffries L Harris M Price SA 1967 Atypical menaquinone pattern in a strain of Staphylococcus aureus Nature 216 808 809 6074952
- Authors
- Wakeman, C. A., Hammer, N. D., Stauff, D. L., Attia, A. S., Anzaldi, L. L., Dikalov, S. I., Calcutt, M. W., & Skaar, E. P.
- Affiliations
- Vanderbilt University Medical Center (US)
- Grove City College (US)
- Cairo University (EG)
- Department of Pathology, Microbiology and Immunology Vanderbilt University Medical Center Nashville TN 37232 USA
- Corresponding author
- Skaar, Eric P.
- ORCID
- Venue
- Molecular Microbiology
- Publisher
- Wiley
- Published
- 2012-10-24
- Volume
- 86
- Issue
- 6
- Pages
- 1376-1392
- ISSN
- 0950-382X (ISSN-L)
- 1365-2958
- PMC
- PMC3524387
- OpenAlex
- W1947356700
- Cited by
- 94
- References
- 70
- Citations by year
- 2026: 6 · 2025: 6 · 2024: 3 · 2023: 3 · 2022: 8 · 2021: 8 · 2020: 7 · 2019: 6 · 2018: 11 · 2017: 11 · 2016: 9 · 2015: 5 · 2014: 7 · 2013: 4
- FWCI
- 3.07
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Molecular Microbiology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Vanderbilt University (P30DK058404)
- Vanderbilt University Medical Center (P30DK058404)
- National Institutes of Health
- National Heart, Lung, and Blood Institute (T32HL069765, HL094296, HL069765, T32HL094296)
- National Institute of Allergy and Infectious Diseases (F32AI100535, AI 069233, AI073843, AI091771, F32AI091244, F32-AI091244-01, R01AI069233, R56AI091771, R01AI073843)
- National Institute of Diabetes and Digestive and Kidney Diseases (P30DK058404)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Bacterial Genetics and Biotechnology
- Health Sciences › Medicine › Infectious Diseases › Antimicrobial Resistance in Staphylococcus
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
- Keywords
- Staphylococcus aureus, menaquinone biosynthesis, superoxide production, oxidative damage, semiquinone, redox cycling, iron acquisition
- MeSH terms
- Adenosine Triphosphatases, DNA Transposable Elements, Heme, Staphylococcus aureus, Superoxides, Mutagenesis, Insertional, Gene Deletion, Oxidative Stress, Vitamin K 2, Biosynthetic Pathways
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