Our proposal directly addresses the Program Announcement (RFA-AI-10-003) goals of """"""""development of broad- spectrum (innate immunity) immunotherapeutic that targets NIAID Priority Agents"""""""" and establishment of """"""""collaborations between researchers in different disciplines and/or with industry"""""""" in a very powerful and unique fashion. Here we will describe our extensive published data revealing the novel function of transcription factor hypoxia inducible factor-1 (HIF-1) as a master regulator of host innate immune function, including proof-of-principle demonstrations that pharmacologic targeting of HIF-1 can augment the bactericidal capacity of phagocytic cells against Gram+ and Gram- bacteria in vitro and in vivo. HIF-1 is induced by bacterial infection, even under normoxia, and regulates the production of key immune effector molecules including granule proteases, antimicrobial peptides, nitric oxide and TNF-a. We then provide exciting new unpublished data that show how potent new-generation prolyl hydroxylase (PHD) inhibitor drugs from Akebia Therapeutics, Inc. boost HIF-1 in human phagocytes and cause them to kill pathogens such as methicillin-resistant Staphylococcus aureus (MRSA) with efficiency comparable to classical antibiotic therapy. Importantly, the same class of agents accelerates wound closing in skin, providing a therapeutic approach for skin and wound infections that promotes healing while simultaneously providing an anti-infective barrier. This innovative antimicrobial treatment strategy, working through the host, is inherently broad spectrum and can be used as an adjunct to classical antibiotic therapy. Rather than designing drugs to target the bacteria, medications that promote HIF-1a activity could be used to boost the bacterial killing ability of white blood cells and promote the resolution of infection through the actions of our natural immune defenses. The research plan will further establish the mechanistic underpinnings for HIF-1 antimicrobial activity by microarray and companion immunogenetic analysis of HIF-1 regulated genes in the context of infection, the role of HIF-1 in protecting against microbial toxin induced phagocyte toxicity and apoptosis, and the involvement of phagocyte extracellular traps in HIF-1 mediated bacterial killing. HIF-1 knockout mice will be used to assess the role of the transcriptional control pathway in control of MRSA and Pseudomonas infections in skin, skin wounds, and pneumonia models of infection. Then, as informed by the results of those studies, treatment trials of HIF-agonist lead compound AKB-4924 against MRSA and P. aeruginosa will be explored in these same models, with topical compared to systemic therapy in the skin and wound models. Through our partnership with Akebia Therapeutics, an extensive preclinical development plan of pharmacokinetic and safety/toxicity analyses will be conducted with the goal of an FDA Investigational New Drug Application for entry into clinical trials of bacterial skin infection, initial as a topical agent. Ultimately, HIF-1 immune boosting therapy could find wide application in the treatment of difficult infections complicated by antibiotic resistance or weakened host defense.
Through our complementary expertise in molecular cell biology and bacterial-host interactions at UCSD, we have discovered a novel role for the transcription factor HIF-1 in regulating the ability of human white blood cells to kill bacteria. Partnering with Akebia Therapeutics, we have shown that pharmacological augmentation of HIF-1 boosts the ability of human cells to kill bacteria such as methicillin-resistant Staphylococcus aureus (MRSA) and reduces staphylococcal infection in vivo. This application presents a development plan to validate this innovative approach to broad-spectrum antibiotic anti-infective therapy and pave its entry into human clinical trials.
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