A multidisciplinary team led by WashU chemists repurposed an antimalarial drug in the fight against antibiotic resistance.
A team of chemists, biologists, and microbiologists led by researchers at WashU have found a way to tweak an antimalarial drug and turn it into a potent antibiotic, part of a project more than 20 years in the making. Importantly, the new antibiotic should be largely impervious to the tricks that bacteria have evolved to become resistant to other drugs. “Antibiotic resistance is one of the biggest problems in medicine,” said Timothy Wencewicz, an associate professor of chemistry. “This is just one step on a long journey to a new drug, but we proved that our concept worked.”
The lead author of the study, John Georgiades, AB ’24, is now a graduate student at Princeton University who took over the project while he was an undergraduate in Wencewicz’s lab. Other co-authors include Joseph Jez, the Spencer T. Olin Professor in Biology; Christina Stallings, a professor of molecular microbiology at the School of Medicine; and Bruce Hathaway, a professor emeritus at Southeast Missouri State University. The findings were published in ACS Infectious Diseases, a journal of the American Chemical Society.
A new approach to antibiotics is sorely needed because many common drugs are losing their punch, Wencewicz said. He points to Bactrim, a combination of the drugs sulfamethoxazole and trimethoprim. Often prescribed to treat ear infections and urinary tract infections, Bactrim blocks a bacteria’s ability to produce folate, an important nutrient for fast-growing germs. “It’s been prescribed so often that resistance is now very common,” Wencewicz said. “For a long time, people have been thinking about what’s going to replace Bactrim and where we go from here.”
Instead of creating new antibiotics out of whole cloth, Georgiades, Wencewicz, and their team used chemistry to tweak cycloguanil, an existing drug used to treat malaria. “It’s a slick way to give new life to a drug that is already FDA-approved,” Wencewicz said. Like Bactrim, cycloguanil works by blocking the enzymes that organisms need to produce folate. It has saved millions of people from malaria over the decades, but it was useless against bacteria because it didn’t have a way to penetrate the membrane that surrounds bacterial cells.
After many trials, researchers were able to attach various chemical keys to cycloguanil that opened the door to the bacterial membrane. Once the new compounds reached the inner workings of the cell, they staged a two-pronged attack on the enzymes that bacteria need to produce folate. “Dual-action antibiotics tend to be much more effective than drugs that just take one approach,” Wencewicz said. Bacteria may be able to evolve resistance to one part of the attack, but they won’t easily find a way to stop both at once, he explained.
The new compound proved to be effective against a wide range of bacteria, including Escherichia coli and Staphylococcus aureus, two of the most common causes of bacterial infections. Unlike Bactrim and other existing drugs that target folate, some of the new compounds also showed power against Pseudomonas aeruginosa, a pathogen that often infects people with weakened immune systems.
Although several compounds showed promise in the lab, Wencewicz knew he had to dig deeper to really complete the mission. “We needed to understand how these compounds were working on a molecular level,” he said. “That’s where John Georgiades stepped in.”
Georgiades, a Beckman Scholar and a Goldwater Scholar during his time at WashU, worked with Jez to use X-ray crystallography to determine the structures of the chemical keys — a crucial step in understanding their antibacterial potential. “We chose a couple of compounds that showed the most potential and really drilled down to investigate their mechanisms,” Georgiades said.
Georgiades also collaborated with Stallings to show that the new compound was effective against Mycobacterium abscessus, an especially hard-to-treat organism that can cause lung infections and other illnesses in individuals with cystic fibrosis. “The collaborative atmosphere at WashU made this project possible,” Georgiades said. “There are more than 20 people on this paper from several institutions, and they all played a part.”
Wencewicz’s role in the project goes back to his time as an undergraduate at Southeast Missouri State University. That’s where he first met Hathaway, a chemist who had been tinkering with antibiotic compounds since his own days as a postdoctoral researcher in the early 1980s. Hathaway, now a professor emeritus of chemistry at SEMO, laid the foundation for this antibiotic development.
“This work breaks new ground on work that started at the beginning of my professional career,” Hathaway said. “Since I have retired, in some ways, this is my crowning achievement. I’m very grateful to Tim and everyone who saw the promise of this line of research and brought it to the next level.”
The collaboration between Wencewicz and Hathaway spanned several institutions and nearly two decades. They were determined to find the right chemical keys to help existing drugs penetrate bacterial membranes. Eventually, Wencewicz amassed a collection of candidate compounds that he carried with him as his career took him to the University of Notre Dame, Harvard, and eventually WashU.
“Antibiotics used to be the backbone of the pharmaceutical industry, but now it’s sort of an orphan class of drugs,” Wencewicz said. “As academics, we can come in, take the risk, and generate the knowledge base that will provide new breakthroughs.”
