Decades-Long Quest Leads to New Antibiotic Compounds
taylorvich writes:
https://phys.org/news/2025-03-decades-quest-antibiotic-compounds.html
A team of chemists, biologists and microbiologists led by researchers in Arts & Sciences at Washington University in St. Louis has 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 in Arts & Sciences. "This is just one step on a long journey to a new drug, but we proved that our concept worked."
The findings are published in ACS Infectious Diseases. 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.
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.
More information: John D. Georgiades et al, Expanding the Landscape of Dual Action Antifolate Antibacterials through 2,4-Diamino-1,6-dihydro-1,3,5-triazines, ACS Infectious Diseases (2025). DOI: 10.1021/acsinfecdis.4c00768
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