Are fungi already resistant to fungicides?

For close to half a century, we’ve relied heavily on fungicides - fungus killing chemicals - to keep our plant crops healthy and our population fed. But, because the molecules that farmers use are the same or extremely similar to the ones that we use in hospitals to treat fungal infection, the high rates of consumption in the environment of these chemicals is driving the inexorable evolution of fungal resistance, with obvious human health consequences. Here’s Mat Fisher at Imperial College London…

Mat - The worst fungal infection on the planet is caused by the very common mould Aspergillus fumigatus. It causes half the global burden of fungal disease—over 2 million cases per year. It kills more people than malaria or tuberculosis. The problem is it’s everywhere in the environment, and that’s where we get exposed to it. It forms mould spores, it’s a bioaerosol, but it’s also exposed to fungicides that farmers use. So what we’ve seen is that Aspergillus has evolved resistance to the same clinical drugs used by doctors, because farmers use the same ones. This is called dual use.

Chris - So the Aspergillus floating around in the air—like the mouldy patch on the ceiling where there's been a leak—that’s probably Aspergillus, isn’t it? Are you saying that the spores it produces, which I could be breathing in, might now be resistant?

Mat - Absolutely. We asked this question: of those spores of Aspergillus, which are soft and blown on the breeze, what proportion have become resistant to frontline clinical antifungals—the azoles? Azoles are also the same fungicides sprayed by farmers. We had a brilliant PhD student, Jen Shelton, who recruited a cohort of citizen scientists to catch fungal spores using little sticky samplers. These were returned in envelopes to our lab. We cultured the mould and calculated the proportion that was resistant. The incredible number she found was that one in 20 spores in the air are now resistant to multiple azole antifungals.

Chris - One in 20? That's 5%! That’s huge.

Mat - Yes, and it wasn’t just a one-off. She repeated the experiment four times over two years—and the number was always the same.

Chris - If we wind the clock back to before we had these drugs, would we still find resistance? Some microbes just happen to be resistant by chance, and we enrich that resistance by using drugs. So if you go back in history, was resistance already there, or have we created it?

Mat - Azoles were introduced in 1980—as fungicides in the environment. That’s when we started seeing resistance markers in the genome. Since then, there's been a steady explosion of resistance, leading to the one-in-20 number we find now.

Chris - What can we do about this? It sounds like human overpopulation and global movement—of people, animals, and plants—have created enormous opportunities for fungi. And with drug use on top of that, even more so. What can we do?

Mat - First, we have to feed the world. To do that, we need food security. Fungicides are wonderful because they let us grow huge amounts of crops—so everyone gets fed. But we have a resistance problem. If you're a patient with azole-resistant invasive aspergillosis, you will die unless given a new therapy. Thankfully, we’ve invented new drugs—two are coming out of phase III clinical trials. They offer hope to patients with resistant infections.

Chris - But won’t we be back to square one? If farmers and others start using those drugs on crops, won’t resistance just evolve again and we’ll have nothing left?

Mat - You’re right. Any new drug that works against fungi won’t just be used in clinical settings. It will also be used in agriculture. And this scenario has already happened. The newest antifungal with a new mode of action is called Olorofim. It’s a brilliant drug for treating invasive aspergillosis. But now it’s being used in the environment with an analogue called Iflifenoquin. This has been registered as a fungicide in the United States. So yes, we’re spinning the roulette wheel of resistance again as this new antifungal starts being used more widely in agriculture.

Chris - And what do the regulators say?

Mat - This drug is currently under scrutiny by the European Union. They’re asking whether it will lead to resistance to Olorofim. If they decide the risk is real, they may ban it in the EU. We're only months away from this decision—so we're on tenterhooks to see which way they go.

Chris - But that's just one jurisdiction. Microbes don’t observe geography—they go where people go. If other countries use this drug freely, resistance that develops there will spread here.

Mat - True. But the EU is a large and influential body. It’s hoped that if they make the right decision, other countries will follow. There are excellent fungicides for use in the environment, but certain modes of action should be reserved for human medicine—or used very intelligently and sparingly. Resistance is often a slow-moving problem. Azole resistance took 20 years to emerge. We have some time here—but we must get it right.