Bacterial Nitric Oxide Synthase Is Required for the Staphylococcus aureus Response to Heme Stress
Open accessAbstract
Staphylococcus aureus is a pathogen that causes significant morbidity and mortality worldwide. Within the vertebrate host, S. aureus requires heme as a nutrient iron source and as a cofactor for multiple cellular processes. Although required for pathogenesis, excess heme is toxic. S. aureus employs a two-component system, the heme sensor system (HssRS), to sense and protect against heme toxicity. Upon activation, HssRS induces the expression of the heme-regulated transporter (HrtAB), an efflux pump that alleviates heme toxicity. The ability to sense and respond to heme is critical for the pathogenesis of numerous Gram-positive organisms, yet the mechanism of heme sensing remains unknown. Compound '3981 was identified in a high-throughput screen as an activator of staphylococcal HssRS that triggers HssRS independently of heme accumulation. '3981 is toxic to S. aureus; however, derivatives of '3981 were synthesized that lack toxicity while retaining HssRS activation, enabling the interrogation of the heme stress response without confounding toxic effects of the parent molecule. Using '3981 derivatives as probes of the heme stress response, numerous genes required for '3981-induced activation of HssRS were uncovered. Specifically, multiple genes involved in the production of nitric oxide were identified, including the gene encoding bacterial nitric oxide synthase (bNOS). bNOS protects S. aureus from oxidative stress imposed by heme. Taken together, this work identifies bNOS as crucial for the S. aureus heme stress response, providing evidence that nitric oxide synthesis and heme sensing are intertwined.
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Bacterial nitric oxide synthase protects S. aureus from heme-induced oxidative stress.
“In addition, bacterial nitric oxide synthase (bNOS) protects S. aureus from heme-induced oxidative stress (Surdel et al., 2016).”
From The Impact of Dietary Transition Metals on Host-Bacterial Interactions (2018) · cites this paper as Surdel et al., 2016
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Background
- Authors
- Surdel, M. C., Dutter, B. F., Sulikowski, G. A., & Skaar, E. P.
- Affiliations
- Vanderbilt University Medical Center (US)
- Vanderbilt University (US)
- United States Department of Veterans Affairs (US)
- Corresponding author
- Skaar, Eric P.
- Venue
- ACS Infectious Diseases
- Publisher
- American Chemical Society (ACS)
- Published
- 2016-07-07
- Volume
- 2
- Issue
- 8
- Pages
- 572-578
- ISSN
- 2373-8227 (ISSN-L)
- PMC
- PMC6610873
- OpenAlex
- W2472379744
- Cited by
- 18
- References
- 37
- Citations by year
- 2026: 1 · 2025: 2 · 2023: 3 · 2022: 2 · 2019: 2 · 2018: 3 · 2017: 4 · 2016: 1
- FWCI
- 2.69
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- ACS Infectious Diseases (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute of Allergy and Infectious Diseases (R01AI069223, R01AI073843)
- 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 › Cell Biology › Hemoglobin structure and function
- Keywords
- Staphylococcus aureus, heme sensing, nitric oxide, oxidative stress, iron acquisition, heme toxicity, small molecule activators
- MeSH terms
- Bacterial Proteins, Biological Transport, Heme, Humans, Nitric Oxide, Staphylococcal Infections, Staphylococcus aureus, Gene Expression Regulation, Bacterial, Nitric Oxide Synthase
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