Symposium Presentation Australian Society for Microbiology Annual Scientific Meeting 2024

Inositol polyphosphate kinases: “new kids on the block” from an antifungal drug targeting perspective? (103540)

Julianne T Djordjevic 1 2 3 , Desmarini Desmarini 1 2 , Bethany Bowring 1 , Pooja Sethiya 1 2 , Philip Thompson 4
  1. Centre for Infectious Diseases & Microbiology , Westmead Institute for Medical Research, 176 Hawkesbury Rd, Westmead NSW 2145, Sydney, NSW, Australia
  2. Sydney Institute for Infectious Diseases, University of Sydney, Sydney, NSW
  3. Western Sydney Local Health District, Westmead Hospital, Sydney, NSW, Australia
  4. Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, Melbourne, Victoria, Australia

World-wide, invasive fungal diseases affect 600 million people and cause >2.5 million deaths annually. A significant contributor to this is the limited variety and compromised effectiveness of available antifungal drug classes. A major challenge is that, as eukaryotic organisms, fungi share many fundamental biological characteristics with human cells. Innovative research to identify suitable discriminatory drug targets to pursue for developing novel antifungal drug classes, is essential to address this unmet global health priority. In response, we discovered that synthesis of the fungal inositol polyphosphate, IP7, is critical for multiple aspects of fungal virulence and occurs via a non-redundant pathway, in contrast to humans. We also proved the feasibility of selectively blocking IP7 synthesis in fungi. An impact on numerous virulence functions, contrasts with the current therapies that block only a single function. In fungi, IP7 is synthesized by sequentially acting inositol polyphosphate kinases (IPK), which diverge from conventional kinases that phosphorylate proteins. Our studies have focused on inhibiting the first IPK in the pathway, Arg1 (IP3-4K), since Arg1 is structurally and functionally different from its closest mammalian counterpart. This work will cover what we have discovered about how fungal Arg1 exerts a pleiotropic role in promoting virulence, and our efforts to create a novel, lead, Arg1-targeting drug, with antifungal properties against two fungal priority pathogens (WHO 2023).