How do we treat fungal diseases?

Our ability to treat fungal diseases is far behind the curve of that of bacteria or even viruses. So, what challenges do the medical mycologists charged with creating the treatments of the future face? I’ve been speaking to the University of Exeter’s Neil Gow…

Neil - There are drugs which are developed against the cell wall. This is a sort of structure which encapsulates the fungus. Bacteria have cell walls, fungi have different cell walls, but humans do not have cell walls. And this is an excellent target because virtually everything in the cell wall of a fungus is not found in human bodies at all. So there's a great opportunity to develop new drugs, and the echinocandins are an existing class of drugs which target the biosynthesis of a critical component of the cell wall, beta-glucan, and these are on the market. There are several versions of the echinocandins which are available for clinicians to use to treat fungal infections.

Chris - Does it matter then what sort of fungus we're talking about, whether it's one that preys on crops or one that might attack a person or an animal? Because they share those similarities, are they likely to be amenable to the same sorts of treatments?

Neil - Well, you're absolutely right. The differences between fungi which cause human infections and those found in the environment, and even those which cause plant infections, are rather slight. And that means that agents which can be used to treat fungal infections often can also be used to treat plant infections. Now, this actually in itself is an issue and a problem, because we now know that azole resistance is a problem which you see in organisms which cause plant disease. But some of those organisms are also organisms which can cause human disease. Therefore, you can get an azole-resistant fungus in the environment, and the spores spread very widely in the air. They even get into hospital settings. They certainly get into patients who have sensitivities or immune deficiencies which make them vulnerable to fungal infections. So they can be pre-colonised or infected by a fungal strain which is already azole-resistant. And that's a major issue for us. So these are the sort of dual-use antifungals: one use in the clinic and one use in agricultural practice to treat crops. And the only two new classes of antifungals which are in development — one's called fosmanogepix and one's called olorofim — these are very exciting new drugs to treat fungal infections clinically. But there are very similar compounds in the same class of agents which are also being trialled in the field to treat diseases of plants. And of course, we are concerned that we may see resistance emerging environmentally which could be transferred again into a clinical setting.

Chris - Are we also creating new opportunities for the fungal world to effectively invade us or exploit us, for instance, by immunosuppressing people who have cancers or organ transplants, or at the same time giving people big doses of antibiotic drugs to treat bacterial infections and, in the process, almost clearing the way for fungi to take over? So are we creating opportunities and creating diseases that didn't exist historically through modern medical practices?

Neil - That's actually a major point in why fungal infections are now becoming much more prevalent. In the past, many people used to succumb to diseases like cancer, but now improvements in their treatment have meant that we can look after and maintain them, and people will survive their cancers. But often their treatment makes them very vulnerable. For example, they might be given a regimen of drugs which reduces their natural immunity. And during that period of vulnerability, cancer patients are exquisitely in danger of being colonised and being infected by a fungus. In fact, many cancer patients cost many thousands of pounds simply providing antifungals to prevent that possibility. And yet most people are very unaware of the threats imposed by fungal infections. So it's come through the ranks and become a major part of the global health protection efforts.

Chris - Do you think then that people are not paying sufficient heed to this? Is this not getting enough attention in your view?

Neil - This programme is one bit of evidence that people are beginning to understand that this is a problem that needs to be addressed. And funders such as the Wellcome Trust and MRC, and other funders of research across the world, are also upscaling their attention to fungal infections, which is very welcome indeed. One issue that remains, though, is because this has been a burgeoning problem, which has expanded considerably in the last 20, 30, 40 years, the population size of researchers who work in medical mycology remains very small. We've not yet caught up with the demand that this topic really requires. Indeed, infectious disease budgets in most parts of the world — only about 2 to 3% of those budgets which are allocated to infectious disease — go to medical mycology. Not because this is not important, not because the funders don't want to fund it, but because there are relatively few medical mycologists like myself putting in grants. What we need is more people on the ground tackling this area.

Chris - So what does the future look like from your perspective then — in the near term and also the long term? Are you worried?

Neil - We are concerned that there are new epidemics emerging and we need to have a response in place to be able to deal with those. I'm also optimistic that the quality of research in this area has been very high, and we are seeing new drug classes being approved. There have been four new drugs authorised in the last 10 years, and there are also several which are in clinical development and at various stages of testing, which should help our position. But we remain blind in a number of ways. For example, as a virologist, I'm sure you'll be appalled to remember that in medical mycology, we don't have a single vaccine — not one vaccine available. Not that we couldn't develop them, but there hasn't been sufficient work to get them on the ground. We still need diagnostics which can ensure that doctors can quickly realise they've got a fungal infection and not a bacterial or a viral infection. And we also need to know a lot more about the immunology of fungal infections so we can develop immunotherapies which can support us. There's a lot of work in the background, but it’ll be a while before it emerges into the clinic for day-to-day use.