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

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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.

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Acknowledgements

We would like to thank Katja Branitzki-Heinemann, Yohan Penny, and Sabina Anik for technical assistance, Drs. Laura Crotty-Alexander and Mary Hensler for advice regarding experimental design, and Dr. Charlotte Hartman for assistance with project planning. Support for this work was provided by NIH grant AI090863 (V.N., R.S.J., R.S.) and USAMRAA award (R.S., V.N.). C.Y.M.O. was supported through the UCSD/SDSU IRACDA Postdoctoral Fellowship Program (GM06852).

Conflicts of interest

R.A. Shalwitz and A. Kotsakis are employees of Aerpio Therapeutics.

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Authors and Affiliations

  1. Department of Pediatrics, University of California, 9500 Gilman Drive, La Jolla, San Diego, CA, 92093, USA

    Cheryl Y. M. Okumura, Andrew Hollands, Dan N. Tran, Joshua Olson, Samira Dahesh, Maren von Köckritz-Blickwede, Wdee Thienphrapa & Victor Nizet

  2. Division of Biological Sciences, University of California, 9500 Gilman Drive, La Jolla, San Diego, CA, 92093, USA

    Courtney Corle, Seung Nam Jeung & Randall S. Johnson

  3. Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, 9500 Gilman Drive, La Jolla, San Diego, CA, 92093, USA

    Victor Nizet

  4. Aerpio Therapeutics, Inc., 9987 Carver Road, Suite 420, Cincinnati, OH, 45242, USA

    Anna Kotsakis & Robert A. Shalwitz

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  1. Cheryl Y. M. Okumura
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Correspondence to Victor Nizet.

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Okumura, C.Y.M., Hollands, A., Tran, D.N. et al. A new pharmacological agent (AKB-4924) stabilizes hypoxia inducible factor-1 (HIF-1) and increases skin innate defenses against bacterial infection. J Mol Med 90, 1079–1089 (2012). https://doi.org/10.1007/s00109-012-0882-3

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