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

J Mol Med (Berl). 2012 Sep;90(9):1079-89. doi: 10.1007/s00109-012-0882-3. Epub 2012 Feb 28.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Anti-Bacterial Agents / therapeutic use*
  • Cell Line
  • Female
  • Humans
  • Hypoxia-Inducible Factor 1 / agonists
  • Hypoxia-Inducible Factor 1 / immunology*
  • Immunity, Innate / drug effects*
  • Keratinocytes / drug effects
  • Keratinocytes / immunology
  • Keratinocytes / microbiology
  • Mice
  • Phagocytes / drug effects
  • Phagocytes / immunology
  • Phagocytes / microbiology
  • Piperazines / pharmacology
  • Piperazines / therapeutic use*
  • Pyridones / pharmacology
  • Pyridones / therapeutic use*
  • 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 / drug effects
  • Staphylococcus aureus / immunology


  • AKB-4924
  • Anti-Bacterial Agents
  • Hypoxia-Inducible Factor 1
  • Piperazines
  • Pyridones