Journal
JOURNAL OF MOLECULAR MEDICINE-JMM
Volume 90, Issue 9, Pages 1079-1089Publisher
SPRINGER
DOI: 10.1007/s00109-012-0882-3
Keywords
Hypoxia inducible factor-1 (HIF-1); Innate immunity; Staphylococcus aureus; Bacterial infection; Antibiotic-resistant bacteria
Funding
- NIH [AI090863]
- USAMRAA award
- UCSD/SDSU IRACDA Postdoctoral Fellowship Program [GM06852]
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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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