How to kill a fungus – and why

MRSA, C. difficile – most of us have become familiar with the ominous alphabet of drug-resistant bacteria. We’ve heard the alarms about the improper use of antibiotics and warnings of a frightening future without drugs to treat strep throat or protect us during routine surgical procedures.

The University of Toronto's Leah Cowen, a professor in the department of molecular genetics and recent winner of a Steacie Memorial Fellowship from the Natural Sciences and Engineering Council, is sounding a slightly different alarm. (Read more about Steacie fellows at U of T.)

“Fungal superbugs are a cause of just as much human mortality worldwide as some bacterial pathogens,” Cowan says. They’re killing about 1.5 million people per year, which is on par with bacterial pathogens such as those causing tuberculosis or the parasites causing malaria.”

Yet drug-resistant fungi don’t get nearly the attention their bacterial cousins do.

“Fungi mostly affect immune-compromised individuals,” she explains. “Most fungal pathogens are opportunistic, so they can only cause disease when provided an opportunity. This means the major patient groups are transplant recipients, people undergoing chemotherapy for cancer treatment and people infected with HIV.”

And that last group of patients means there is a global inequity in terms of who is hardest hit by fungal superbugs.

“The global burden is much greater in places like sub-Saharan Africa,” she says. “Fungal superbugs don’t rank as much of a threat to the average North American or European, so there’s less media attention. We didn’t get nearly as concerned about Ebola, for example, until it came to North America and Europe.”

To make matters worse, fungi are hard to kill, and that’s because they have a lot in common with their human hosts. Like us, fungi are eukaryotes. This means our cells are organized similarly, containing a nucleus and a series of organelles, which are smaller membrane-enclosed structures inside the cell that perform specific functions. Fungi and humans also have similar sets of genes and cellular processes.

Because of these similarities, when you try to kill a fungus, you often end up introducing disastrous side effects in the human host. Many bacteria, on the other hand, are relatively easy to kill. As a result, while we have a dozen or so classes of antibiotics, there are only three classes of anti-fungal drugs. And fungi are quickly developing resistance to them.

Cowen, who holds the Canada Research Chair in Microbial Genomics and Infectious Disease, wants to know exactly how this happens, so she is investigating how fungal pathogens cause disease and how they evolve resistance to the drugs we use to try to kill them.

A believer in the importance of both fundamental and applied research, Cowen complements her exploratory work with drug development. She’s particularly focused on a protein called HSP90, which is known as a chaperone protein.

“Inside cells, it’s incredibly crowded,” she says. “People often don’t appreciate this. You get images from biology textbooks, and it looks like each protein is doing its own thing and has its own space. In reality, a cell is a very densely packed environment. Proteins bump into each other all the time and engage in what people call promiscuous interactions – interacting with proteins they’re not supposed to be interacting with.”

Enter HSP90. Like a chaperone at a dance urging hormone-happy teenagers not to stand too close, HSP90’s job is to make sure these promiscuous interactions don’t happen. It has long been known that HSP90 plays a role in cancer, but Cowen discovered during her post-doctoral fellowship that it is also critical in facilitating drug resistance in fungal pathogens.

“If you inhibit HSP90, you can reverse drug resistance of many fungal pathogens,” she says. “You can also block new resistance from emerging. We also discovered that it is a key regulator of many facets of biology that is required to cause disease. As a chaperone, it regulates the function of many key circuit points in the cell – it basically allows the cell to function.”

In other words: stop the chaperone, stop the disease.

The tricky part, though, is that this chaperone protein has a counterpart in the human cell. The challenge is to figure out how to disable it in fungi and not in humans.

“We are developing molecules that can go in and selectively target the fungal protein with minimal effects on the human protein.”

Fungi, says Cowen are “understudied and underappreciated.” In addition to threatening human health, they pose a major threat to plants and agriculture – fungi are responsible for the Irish potato famine and Dutch elm blight.

“I was always very interested in the microbial world around me,” she says when asked about the origins of her interest in bacteria’s less famous cousin.

“I did my undergraduate in microbiology and immunology in part because I thought microbes provide fantastic systems to address scientific questions. They reproduce really quickly. They’re the most abundant organisms on the planet. They outnumber human cells in our own bodies by an order of magnitude. They influence all aspects of human health and ecosystem health. Yet they’re so tractable in the lab. You can come up with an idea, do an experiment, and have an answer in a couple days.”

“These life forms have a huge impact on every aspect of our planet.”

Jenny Hall is a writer with the office of the vice-president, research and innovation, at the University of Toronto.