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

作者：Okumura Cheryl Y M; Hollands Andrew; Tran Dan N; Olson Joshua; Dahesh Samira; von Koeckritz Blickwede Maren; Thienphrapa Wdee; Corle Courtney; Jeung Seung Nam; Kotsakis Anna; Shalwitz Robert A; Johnson Randall S; Nizet Victor^*

来源：Journal of Molecular Medicine-JMM, 2012, 90(9): 1079-1089.

DOI：10.1007/s00109-012-0882-3

• Hypoxia inducible factor-1 (HIF-1)
• Innate immunity
• Staphylococcus aureus
• Bacterial infection
• Antibiotic-resistant bacteria

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.

• 出版日期2012-9