A new pharmacological agent (AKB-4924) stabilizes hypoxia inducible factor-1 (HIF-1) and increases skin innate defenses against bacterial infection
Open accessAbstract
Hypoxia inducible factor-1 (HIF-1) is a transcription factor that is a major regulator of energy homeostasis and cellular adaptation to low oxygen stress. HIF-1 is also activated in response to bacterial pathogens and supports the innate immune response of both phagocytes and keratinocytes. In this work, we show that a new pharmacological compound AKB-4924 increases HIF-1 levels and enhances the antibacterial activity of phagocytes and keratinocytes against both methicillin-sensitive and methicillin-resistant strains of Staphylococcus aureus in vitro. AKB-4924 is also effective in stimulating the killing capacity of keratinocytes against the important opportunistic skin pathogens Pseudomonas aeruginosa and Acinetobacter baumanii. The effect of AKB-4924 is mediated through the activity of host cells, as the compound exerts no direct antimicrobial activity. Administered locally as a single agent, AKB-4924 limits S. aureus proliferation and lesion formation in a mouse skin abscess model. This approach to pharmacologically boost the innate immune response via HIF-1 stabilization may serve as a useful adjunctive treatment for antibiotic-resistant bacterial infections.
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HIF activators potentiate innate antibacterial defense mechanisms in in vivo models.
“HIF activators have been used in a variety of in vivo models, where they have been shown to potentiate innate antibacterial defense mechanisms [116]”
From Hypoxia and hypoxia-inducible factors as regulators of T cell development, differentiation, and function (2013) · cites this paper as [116]
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References 48 · Cited by 115
- Authors
- Okumura, C. Y. M., Hollands, A., Tran, D. N., Olson, J., Dahesh, S., von Köckritz-Blickwede, M., Thienphrapa, W., Corle, C., Jeung, S. N., Kotsakis, A., Shalwitz, R. A., Johnson, R. S., & Nizet, V.
- Affiliations
- University of California San Diego (US)
- Aerpio Pharmaceuticals (United States) (US)
- Corresponding author
- Nizet, Victor
- ORCID
- Venue
- Journal of Molecular Medicine
- Published
- 2012-02-28
- Volume
- 90
- Issue
- 9
- Pages
- 1079-1089
- ISSN
- 0946-2716 (ISSN-L)
- 1432-1440
- PMC
- PMC3606899
- OpenAlex
- W2078721739
- Cited by
- 115
- References
- 48
- Citations by year
- 2026: 3 · 2025: 2 · 2024: 4 · 2023: 5 · 2022: 7 · 2021: 8 · 2020: 8 · 2019: 5 · 2018: 9 · 2017: 8 · 2016: 20 · 2015: 9 · 2014: 12 · 2013: 12 · 2012: 3
- FWCI
- 3.92
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Journal of Molecular Medicine (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Wellcome Trust (092738/Z/10/Z)
- National Institutes of Health
- National Institute of General Medical Sciences (GM06852)
- National Institute of Allergy and Infectious Diseases (R01AI093451, R56AI090863, AI090863)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Health Sciences › Medicine › Infectious Diseases › Antimicrobial Resistance in Staphylococcus
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Bacterial biofilms and quorum sensing
- Keywords
- HIF-1, skin innate immunity, Staphylococcus aureus, methicillin-resistant Staphylococcus aureus, Pseudomonas aeruginosa, Acinetobacter baumannii, keratinocytes, phagocytes, antibacterial activity, skin abscess, antibiotic-resistant bacterial infections, adjunctive therapy
- MeSH terms
- Animals, Anti-Bacterial Agents, Cell Line, Female, Humans, Immunity, Innate, Phagocytes, Piperazines, Pyridones, Skin, Staphylococcal Infections, Staphylococcus aureus, Keratinocytes, Skin Diseases, Bacterial, Mice, Hypoxia-Inducible Factor 1
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