Discovery opens the door for new antifungal drugs

New treatments urgently needed to help the 6 million people affected by invasive fungal infections each year

A study published in the journal ACS Infectious Diseases has established that an inositol polyphosphate kinase (IPK) inhibitor, DT-23, could be the key to creating a new class of urgently needed antifungal drug that works differently to current therapies. When used with existing drugs, DT-23 could help to reduce their toxicity.

Invasive fungal infections are a major health concern globally, affecting more than 6 million people worldwide each year and resulting in approximately 2.5 million deaths annually.[1]

A major factor contributing to the high rate of morbidity and mortality associated with invasive fungal disease is the limitations associated with existing antifungal therapies. These drugs are limited by toxicity, a lack of broad-spectrum anti-fungal activity and the development of drug resistance.

Researchers, led by recent PhD graduate Dr Desmarini Desmarini and Associate Professor Julie Djordjevic from WIMR’s Centre for Infectious Diseases and Microbiology, in collaboration with Monash University, have developed DT-23, the first lead inhibitor that works against fungal IPK. They have shown that DT-23 has antifungal activity against the meningitis causing fungal pathogen Cryptococcus neoformans.

Dr Desmarini discovered that DT-23 has dual-targeting action within a fungal IPK pathway that could prevent fungi from becoming resistant to the drug.

“Targeting two IPKs within the pathway at the same time has the potential to reduce the likelihood of treatment resistance, which has already occurred in some of the mainstay drug classes used to treat deadly fungal infections in the clinic,” said Dr Desmarini.

Associate Professor Djordjevic added, “We discovered that, at low doses, DT-23 is more effective when used together with another mainstream antifungal, Amphotericin B (AmB), which is associated with kidney toxicity. In fact, the DT-23/AmB combination worked more effectively than the standard combination therapy used in the clinic to treat C. neoformans infections.”Using transcription profiling, fungal biologist and bioinformatician, Dr Pooja Sethiya showed that DT-23impacts early steps in the IPK pathway, which is consistent with its targeted effect.

The team recently established a collaboration with Vanderbilt University to determine the structure of fungal IPKs, which will facilitate the design of even more effective inhibitors for implementation into clinical practice.