April 6, 2023  Print

Researchers at The Westmead Institute for Medical Research (WIMR) have discovered that a balanced phosphate level in fungi is essential to cause deadly infection in human blood, brain and lungs.

The research team is hopeful that destroying the fungi’s ability to get the phosphate balance “just-right” could stop fungal infection and provide a new avenue for antifungal drug development.
Too little phosphate stops fungi from producing energy and replicating. Too much phosphate makes fungi sick by causing metals to accumulate and by reducing the fungi’s ability to cope with the high temperature of the human body.
Lead researcher, Associate Professor Julianne Djordjevic said, “Our research team previously found that the fungal protein Pho81 was needed to increase phosphate intake and that without Pho81, the fungi could not grow or establish an infection. On the other hand, new research shows that the fungal protein Pho80 is required to turn off the import of phosphate. Without Pho80, the fungi accumulate too much phosphate leading to reduced ability to infect and establish a brain infection.”
This research was performed on the fungus, Cryptococcus neoformans, which was just classified by the World Health Organisation (WHO) as a “critical” priority fungal pathogen. It causes life-threatening brain infections in patients with weakened immune systems, such as those with leukaemia and AIDS, as well as organ transplant recipients on immunosuppressive therapy.
“Invasive fungal diseases pose a serious threat to human health globally with fungal infections killing 150 people per hour,” said co-first author Bethany Bowring.
“In fact, death rates due to fungal blood infections are similar to those of tuberculosis and greater than those due to malaria.
“Although new antifungal drugs are desperately needed to reduce the high global morbidity and mortality of infectious fungal diseases, no new classes of drug have been introduced into clinical medicine since 1986.”
Co-first author Dr Pooja Sethiya expanded on this. “Current antifungal therapies are limited by their toxicity when used for long periods and the fact that fungi are developing resistance to them, similar to how bacteria have become resistant to antibiotics. Finding new drug targets in fungal cells is both a challenge and a major health priority.
“This is because fungal cells share more similarities with human cells compared to other disease-causing microorganisms such as bacteria and viruses. One key difference is how phosphate levels are controlled.”
Research leader, Associate Professor Julianne Djordjevic said, “The proteins Pho81 and Pho80 are both essential for the fungi to maintain the correct levels of phosphate. Too little or too much phosphate reduces the ability of the fungi to cause deadly infections. These proteins are therefore potential targets for the development of new antifungal drugs.

“As human cells do not contain Pho81 or Pho80, inhibiting these proteins using new drugs should have little to no adverse side effects on the patient.

“Disrupting the ability of fungi to maintain a balance of the essential nutrient phosphate opens a new treatment opportunity against fungal diseases.”

The research was published in the journal mBio.