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 dissemination^1-3. The direct products of fungal Arg1, IP_4/5, 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.