A new pharmacological agent (AKB-4924) stabilizes hypoxia inducible factor-1 (HIF-1) and increases skin innate defenses against bacterial infection

• Published in: Journal of molecular medicine (Berlin, Germany) Vol. 90; no. 9; pp. 1079 - 1089
• Main Authors: Okumura, Cheryl Y. M., Hollands, Andrew, Tran, Dan N., Olson, Joshua, Dahesh, Samira, von Köckritz-Blickwede, Maren, Thienphrapa, Wdee, Corle, Courtney, Jeung, Seung Nam, Kotsakis, Anna, Shalwitz, Robert A., Johnson, Randall S., Nizet, Victor
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer-Verlag 01.09.2012; Springer; Springer Nature B.V
• Subjects: Abscesses; Acinetobacter; Adaptations; Animal models; Animals; Anti-Bacterial Agents - therapeutic use; Antibacterial activity; Antimicrobial activity; Biological and medical sciences; Biomedical and Life Sciences; Biomedicine; Cell Line; Drug resistance; Energy balance; Female; General aspects; Human Genetics; Humans; Hypoxia-inducible factor 1; Hypoxia-Inducible Factor 1 - agonists; Hypoxia-Inducible Factor 1 - immunology; Immune response; Immunity, Innate - drug effects; Infection; Internal Medicine; Keratinocytes; Keratinocytes - drug effects; Keratinocytes - immunology; Keratinocytes - microbiology; Medical sciences; Medicin och hälsovetenskap; Mice; Molecular Medicine; Original Article; Oxygen; Pathogens; Phagocytes; Phagocytes - drug effects; Phagocytes - immunology; Phagocytes - microbiology; Piperazines - pharmacology; Piperazines - therapeutic use; Pseudomonas aeruginosa; Pyridones - pharmacology; Pyridones - therapeutic use; Skin; Skin - drug effects; Skin - immunology; Skin - microbiology; Skin Diseases, Bacterial - immunology; Skin Diseases, Bacterial - prevention & control; Staphylococcal Infections - immunology; Staphylococcal Infections - prevention & control; Staphylococcus aureus; Staphylococcus aureus - drug effects; Staphylococcus aureus - immunology; Stress; Transcription factors; Bacterial infection; Innate immunity; Antibiotic-resistant bacteria; Hypoxia inducible factor-1 (HIF-1); Treatment resistance; Stability; Natural immunity; Increase; Organism defense; Infection; Medicine; Antibiotic; Bacteriosis; Bacteria; Micrococcales; Micrococcaceae; Transcription factor HIF1; Skin; Antibacterial agent; Physicochemical properties; Staphylococcus aureus
• ISSN: 0946-2716; 1432-1440; 1432-1440
• DOI: 10.1007/s00109-012-0882-3

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.