Previous generations of scientists sifted through soil or ground up jungle plants to discover antibiotics that have saved hundreds of millions of lives. But they may be exhausting their sources. "We keep discovering the same ones all the time," Wilfred van der Donk says.
Now van der Donk is taking a 21st century approach to discovering new antibiotics by using modern tools like genome databases. He hopes the next generation of antibiotics can help overcome the ever-expanding problem of pathogens' resistance to most common antibiotics. "There is relatively little discovery effort being made by industry, so our new methods of antibiotic discovery—including looking at new classes of compounds—may provide answers toward solving this problem," says the chemist at the University of Illinois at Urbana-Champaign.
Although he's intensely focused on this fundamental research, which he calls an arms race with the microbes, van der Donk is equally committed to inspiring students—in both the classroom and the laboratory—to become excited about science. "At a large university, one can reach a broad audience of talented students. And, hopefully, some will be the next generation of research scientists."
That's how it happened for van der Donk, who caught "science enthusiasm" in high school. "It was the laboratory part of chemistry (called prakticum in Dutch) that attracted me." He earned his bachelor's and master's degrees at Leiden University, the oldest Dutch university. While at Leiden, he heard that Rice University in Houston had put out a special call for graduate students and he applied. "Perhaps it was the general desire of the Dutch to see more of the sun that made this prospect attractive," he quips.
During his early studies, van der Donk was interested in using metals in organic chemistry. A conference around that time introduced him to many of the top people and ideas that could join biology and chemistry. "I was fascinated and inspired by outstanding talks on applying chemical principles to biological problems."
Van der Donk's lab uses organic chemistry, molecular biology, and biochemistry to study enzymes—proteins that carry out chemical reactions in cells. One enzyme his lab studied has been licensed to several pharmaceutical companies to help them create new drug compounds.
But as an HHMI investigator, van der Donk wants to focus more on the problem of antibiotic resistance and creating new antibiotics. The issue isn't really finding new antibiotics. "Using our new approaches, we find new antibiotics, but the important question is how to turn them into medically useful antibiotics." Van der Donk says that the chemical complexity of some of the natural antibiotic compounds makes it difficult to produce them via traditional "medicinal chemistry" methods.
His lab focuses on two types of antibiotics that haven't been studied much for therapeutic use in humans. One group are the lantibiotics, a category that includes nisin, which has been in wide use in food preservation for decades without microbes developing significant resistance or making it less potent. However, nisin doesn't last long in the bloodstream. Scientists have had a hard time making it more stable: changing one piece of the nisin molecule may improve its stability, but building it in the lab required more than 60 separate chemical reactions, making it impractical to produce similar products as a drug. Van der Donk's lab has devised a way to re-create in a test tube the efficient system bacteria use to prepare lantibiotics. They modify a DNA-encoded protein with just two enzymes, which break 16 chemical bonds and create 10 new ones for nisin. By varying the starting materials the enzymes are allowed to work with, his lab has developed a pool of analogs of lantibiotics that they can use to look for a long-lasting antibiotic.
In addition, van der Donk's lab has been searching existing DNA databases, which now include the genomes of more than 700 microbes, for new antibiotics. There, they have found genes to make compounds that may become the next generation of antibiotics.