title: A new pharmacological agent (AKB-4924) stabilizes hypoxia inducible factor-1 (HIF-1) and increases skin innate defenses against bacterial infection.
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.
authors.affiliation: Department of Pediatrics, University of California, 9500 Gilman Drive, La Jolla, San Diego, CA 92093, USA.
authors.forename: Cheryl Y M
authors.initials: CY
authors.lastname: Okumura
authors.forename: Andrew
authors.initials: A
authors.lastname: Hollands
authors.forename: Dan N
authors.initials: DN
authors.lastname: Tran
authors.forename: Joshua
authors.initials: J
authors.lastname: Olson
authors.forename: Samira
authors.initials: S
authors.lastname: Dahesh
authors.forename: Maren
authors.initials: M
authors.lastname: von Köckritz-Blickwede
authors.forename: Wdee
authors.initials: W
authors.lastname: Thienphrapa
authors.forename: Courtney
authors.initials: C
authors.lastname: Corle
authors.forename: Seung Nam
authors.initials: SN
authors.lastname: Jeung
authors.forename: Anna
authors.initials: A
authors.lastname: Kotsakis
authors.forename: Robert A
authors.initials: RA
authors.lastname: Shalwitz
authors.forename: Randall S
authors.initials: RS
authors.lastname: Johnson
authors.forename: Victor
authors.initials: V
authors.lastname: Nizet
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000627:therapeutic use*; D002460:Cell Line; D005260:Female; D006801:Humans; D051793:Hypoxia-Inducible Factor 1 / Q000819:agonists / Q000276:immunology*; D007113:Immunity, Innate / Q000187:drug effects*; D015603:Keratinocytes / Q000187:drug effects / Q000276:immunology / Q000382:microbiology; D051379:Mice; D010586:Phagocytes / Q000187:drug effects / Q000276:immunology / Q000382:microbiology; D010879:Piperazines / Q000494:pharmacology / Q000627:therapeutic use*; D011728:Pyridones / Q000494:pharmacology / Q000627:therapeutic use*; D012867:Skin / Q000187:drug effects / Q000276:immunology / Q000382:microbiology*; D017192:Skin Diseases, Bacterial / Q000276:immunology / Q000517:prevention & control*; D013203:Staphylococcal Infections / Q000276:immunology / Q000517:prevention & control; D013211:Staphylococcus aureus / Q000187:drug effects / Q000276:immunology
chemical_list: C575838:AKB-4924; D000900:Anti-Bacterial Agents; D051793:Hypoxia-Inducible Factor 1; D010879:Piperazines; D011728:Pyridones