How to tame a toxic yet life-saving antifungal

**SPEAKER_1** (0:00)
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**SPEAKER_1** (1:03)
Nature.

**Benjamin Thompson** (1:08)
Welcome back to The Nature Podcast. This week, reducing the toxic side effects of a vital anti-fungal drug and the mystery of Phosphorus at the Milky Way's edge.

**Nick Petruchow** (1:19)
I'm Nick Petruchow.

**Benjamin Thompson** (1:20)
And I'm Benjamin Thompson.
Each year, it's estimated that well over a million people die as a result of an invasive fungal infection. This figure is comparable with deaths caused by malaria or TB, but historically, fungal infections have had much less funding and research attention than other infectious diseases. As a result, treatment options for severe fungal infections are often limited. One drug is amphotericin B, an antifungal developed in the late 1950s. It's a drug with a lot of positives. It's broad spectrum, meaning it'll kill many fungal species, and resistance to it is rare.
However, it has some incredibly serious downsides, so it's only really used as a drug of last resort to treat the most life-threatening infections. This week in Nature, a team of researchers have altered the molecular structure of amphotericin B in an attempt to curb one of its worst side effects. To find out more, I called up Marty Burke from the University of Illinois at Urbana-Champaign, one of the researchers on the paper. Before we talked about how they tweaked the drug, Marty told me about some of the issues with amphotericin B.

**Marty Burke** (2:40)
The problem is it's highly toxic. So when I was doing my own medical school rotations, we used to call it amphoterrable, because its impact on the patients is so severe, there's a short-term toxicity immediately when you give it to a patient, they get kind of almost like an intense flu-like reaction. It's a very unpleasant experience.
But more importantly, long-term, it's very toxic to the kidneys.
And this has been its biggest problem. And many cases that preclude the doctor giving you enough of the medicine to take care of the infection. You're stuck in this situation where you give too much, you can irreversibly impact the kidneys. And if you don't give enough, then the patient doesn't get cured. So kidney toxicity is the big problem. And that's the one that we decided to hone in on.

**Benjamin Thompson** (3:23)
And I guess to get a sense of why this toxicity was happening, it almost comes back to the mode of action of this drug then, and actually how it affects fungi themselves.

**Marty Burke** (3:32)
Yes. So in previous work, we had discovered that different than everybody thought, the amphotericin kills the fungi by forming a sponge on the surface. And then it rapidly extracts what's called a sterol molecule or a greasy molecule. It's important for the membrane. It extracts that molecule into the sponge and thereby kills the fungus.
And so this sponge-like mechanism gave us a new understanding of the killing effects, which therefore gave us a new opportunity to think about how we might make the molecule better.

**Benjamin Thompson** (4:02)
And so the sterol molecule in the fungal cell membranes is called agosterol. And there's a similar molecule in the membranes of human cells, and that is cholesterol. And you wanted to see what the relationship was between the two.

**Marty Burke** (4:12)
Yes, so in this paper, we were able to show for the first time that same sponge-like mechanism is how it's killing the kidney cells.
And so this is the example you just gave. Cholesterol is the human version of that same sterol, and this molecule forms sponges and extracts cholesterol from the human kidney cells and thereby kills them.

**Benjamin Thompson** (4:33)
So you have this antifungal that acts like a sponge, almost sort of tearing cholesterol out of human cell membranes, which is why it's toxic. And that could be the end of the story, but you've tried to avoid that happening in the first instance by tweaking this molecule. What did you do there?

**Marty Burke** (4:47)
So once we understood how it was killing kidney cells, this put us in a very exciting position to change that, so that it still kills the fungal cells, but hopefully doesn't kill the human cells.
And what started to look very promising is that we understood through additional studies that it binds the fungal sterile very strong, it binds the human sterile, but it's weaker. So we had this kind of thought that what if we could mess the binding up a little bit so that it loses its ability to bind the human sterile, but because it binds the fungal sterile so strongly, even if we mess it up a little bit, it'll still bind. So we did what's called a controlled destabilization. And by doing that, we were able to show we could no longer detect any binding to human cholesterol, and yet we still saw good binding, less, but good binding to the fungal sterile. That was an important step forward, but it wasn't enough.