University of Oklahoma natural product chemist finds novel molecules in unexpected places

It pains Robert Cichewicz to admit it, but as a college student, he found chemistry classes boring—full of rote memorization about reactions and reagents that seemed to have little applicability to his life. His first research endeavor as an undergraduate was in anthropology: he investigated the role of chili peppers in Mesoamerican culture, history, and medicine. That sparked a lifelong interest in plants and, ultimately, the compounds they produce. Today, while his interest in botany remains, Cichewicz has made a name for himself as a natural products chemist who searches off the beaten path for interesting structures and potential uses for them.

When Cichewicz, a professor at the University of Oklahoma, became interested in natural products present in the microbiome, he looked not to humans but to other mammals, collecting microbes from roadkill that he and his students gathered. After noticing that standard fungal culture techniques tended to yield the same old metabolites, his team discovered a way to encourage more varied secondary metabolite production by growing mats of fungi on Cheerios. And when one metabolite seemed to have a particularly unusual structure, Cichewicz and his lab probed deeply and found it had a surprising ability to neutralize skunk odor. Lauren Gravitz spoke with Cichewicz about his work and how the natural products field keeps pushing him to turn up surprises.

How did someone not interested in chemistry end up as a natural products chemist?

When I was talking to my master’s adviser in pharmaceutical sciences, I kept asking questions: “What makes this plant do that? And what makes it do this?” And the answer was always a compound. It was never some undefined characteristic of a plant but a specific compound. It was chemistry. My adviser pointed out that everything I was asking about comes back to a chemical principle: What is the compound? What is that structure? Where are the atoms? What is it that they create? I hadn’t taken chemistry beyond the basic requirements, so he had me sit in on undergraduate chemistry courses and take the graduate chemistry courses.

What was your vision when you started your own lab?

At the time, it was not to do what others were doing. It’s still a central tenet of what we do: we look for where there are gaps in what the natural products community is looking at. At the time, looking across the landscape, most people were looking at plants and microbes, so it seemed to me that fungi were the wild west of natural products, where there was a lot more unknown territory.

What’s the latest thing you’ve found on the frontier of fungi?

We’re working on an antifungal called percephacin. It came from a fungus that was growing on a plant here on campus. Structurally speaking, it doesn’t look like any previously reported antifungal, so I think we have something significant.

Our lab knows someone who had gotten a horrible fungal eye infection. He spent 3 months treating his eye every 3 h, and if he slept through a single dose, it would come raging back. So we tested this new antifungal in the lab to see if it would inhibit the fungi that cause these eye infections. It killed them all. When we tested it in corneas removed from pig eyes, it was more potent than some drugs and hit some pathogens that current drugs don’t.

Tell me about the citizen science work you do.

Our citizen science work started as a way to expand our fungi library. We asked people to send in soil samples. It went viral in 2012, and we got several thousand requests to participate. It’s now become a major part of our lab. It even led to an exhibit at Science Museum Oklahoma. We created videos on fungi, artwork made of fungi, displays, and educational panels. As a scientist, you’re lucky if you can get 14 people to read your paper, but we’ve had a quarter-million or more people look at that exhibit.

This citizen science project turned up a fungal compound that you eventually determined could neutralize skunk odor. How did you end up there?

That project was one of the most fun because it started off dealing with cancer drug discovery. And that led to a question about how the molecule was being made. And in trying to figure that out, we stumbled upon the role this molecule is actually playing—it attacked noxious molecules from other fungi and neutralized them. And then we translated that into applications for a human need, which is skunk-odor neutralization. That is just the perfect long-term story of how idea begets idea begets idea, if you’re just willing to look.

What are you working on right now?

The pericosine stuff—the deskunking compound—is still just thrilling. We’ve still got a lot more tricks to learn. A small company here in Oklahoma City is trying to develop the technology, and they’ve been asking for our help to guide some of these initial scientific hurdles. For instance, we know how to make a gram of it in a few weeks. But how do you go from making a few grams in the lab to literal tons of it? This is the part I find both fun and frustrating, the conversion where the natural product becomes a potential commodity chemical and how one goes about getting from that to commercial product on the shelf.

What are your first questions when you start, or one of your students starts, a project?

One is that when we look down the road, if everything works out as you expect, what’s the product of this going to look like? Envision what the outcome is. It doesn’t have to get there—ideas can be wrong. But you better at least have a dream, because if you aren’t dreaming at the beginning, then you’re certainly going to be asleep by the end.

Lauren Gravitz is a freelance writer. A version of this story first appeared in ACS Central Science: cenm.ag/cichewicz. This interview was edited for length and clarity.