1. A new pharmacological agent (AKB-4924) stabilizes hypoxia inducible factor-1 (HIF-1) and increases skin innate defenses against bacterial infection.
- Author
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Okumura CY, Hollands A, Tran DN, Olson J, Dahesh S, von Köckritz-Blickwede M, Thienphrapa W, Corle C, Jeung SN, Kotsakis A, Shalwitz RA, Johnson RS, and Nizet V
- Subjects
- Animals, Cell Line, Female, Humans, Hypoxia-Inducible Factor 1 agonists, Keratinocytes drug effects, Keratinocytes immunology, Keratinocytes microbiology, Mice, Phagocytes drug effects, Phagocytes immunology, Phagocytes microbiology, Piperazines pharmacology, Pyridones pharmacology, Skin drug effects, Skin immunology, Skin Diseases, Bacterial immunology, Staphylococcal Infections immunology, Staphylococcal Infections prevention & control, Staphylococcus aureus drug effects, Staphylococcus aureus immunology, Anti-Bacterial Agents therapeutic use, Hypoxia-Inducible Factor 1 immunology, Immunity, Innate drug effects, Piperazines therapeutic use, Pyridones therapeutic use, Skin microbiology, Skin Diseases, Bacterial prevention & control
- Abstract
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.
- Published
- 2012
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