Invited Speaker Australian Society for Microbiology Annual Scientific Meeting 2018

Virulence-promoting non-protein kinases: Mechanism of action and exploitation as antifungal drug targets (#139)

Sophia Lev 1 , Philip Thompson 2 , Julianne Djordjevic 1
  1. Centre for Infectious Diseases & Microbiology , Westmead Institute for Medical Research, 176 Hawkesbury Rd, Westmead NSW 2145, Sydney, NSW, Australia
  2. Medicinal Chemistry , Monash Institute of Pharmaceutical Sciences, Parkville 3052, Melbourne, Victoria, Australia

Invasive fungal disease (IFD) poses a serious threat to human health, especially in patients immunocompromised by HIV infection or blood cancer therapy, and in organ transplant recipients. IFD affects 300 million people and causes 1.6 million deaths annually. Current antifungals are toxic, sub-optimally effective or poorly absorbed and resistance is emerging. Although novel therapies are needed urgently, no new drug classes have been introduced into clinical medicine since the echinocandins in 1986. Using the genetically tractable and major fungal pathogen, Cryptococcus neoformans, as a model, we showed that the inositol polyphosphate kinase (IPK), Arg1, is critically linked to virulence and IFD and potentially serves as a novel antifungal drug target1. Arg1 is the first of a series of IPKs acting sequentially to convert IP3 to IP7, a key metabolite that promotes fungal stress tolerance, metabolic adaptation and dissemination1-3. The direct products of fungal Arg1, IP4/5, also convey essential virulence-associated functions, including high temperature tolerance, capsule production and normal N-linked mannosylation of enzymes involved in cell wall integrity1. We present evidence that the products of Arg1 promote fungal virulence by altering gene expression via direct interaction with key regulatory proteins. Work is also presented providing proof-of-principle that compounds can be developed that target fungal Arg1, but not mammalian IP3 kinases, and hence are selective for fungi.

References: 1. Li C, Lev S, et al. Virulence 2017;8:1833. 2. Lev S, et al, mBio. 2015;6(3), 3. Li C, Lev S, et al Sci. Rep. 2016;6:23927.