Antibiotic resistance is considered one of the most urgent health threats of our time. Common bacteria such as E. coli and Staphylococcus aureus are evolving defenses against the drugs doctors rely on most. To combat the threat, scientists are racing to find new ways to halt bacterial growth without triggering resistance too quickly.
In recent research, Cornell biologists identified a surprising mechanism that weakens bacteria from within-an insight that could guide the next generation of antibiotics as drug resistance rises worldwide. Researchers at the Weill Institute for Cell and Molecular Biology found that when certain sugar-phosphate molecules pile up inside bacteria, they block a key step in building the bacterial cell wall. Without a strong wall, bacteria cannot survive.
The study, led by Megan Keller, postdoctoral fellow in the laboratory of Tobias Dӧrr, associate professor and director of graduate studies of Microbiology in the College of Agriculture and Life Sciences, was published in the American Society for Microbiology journal mBio in July 2025.
The team studied Vibrio cholerae, the water-borne bacterium that causes cholera disease, yet also possesses the ability to withstand specific antibiotics for an extended period of time. By engineering strains that accumulated certain sugar-phosphates, the scientists noticed dramatic growth defects. Chemical analysis revealed that these sugar-phosphates directly interfered with the enzymes that create peptidoglycan-the rigid mesh that forms the bacterial cell wall.
The interference was specific and powerful: when sugar-phosphate levels rose, the cell wall could not form properly. Instead, bacteria became fragile and prone to bursting. Importantly, the effect mimicked the action of existing antibiotics that also target cell wall synthesis, but through a completely different mechanism, one that may reduce the formation of antibiotic resistance.
The research included contributions from collaborators at Weill Cornell Medicine, with expertise spanning metabolomics, genetics, and biochemistry. The findings offer a new angle for antibiotic development. Instead of designing drugs that directly attack bacterial enzymes, scientists might create compounds that cause sugar-phosphate molecules to accumulate to toxic levels.
"In a way this is an ideal situation," Keller said. "We shut down the bacterium's ability to eat sugar, while at the same time, sensitize it to cell-wall targeting antibiotics. This will make it harder for them to develop resistance." That strategy could bypass existing resistance pathways and provide a fresh line of defense against "superbugs."
Because peptidoglycan is essential for virtually all bacteria but absent in human cells, therapies based on this mechanism could be potent-killing bacteria without harming patients. However, this therapeutic approach could also kill beneficial microbes with the same process.
"This work shows us that bacteria carry the seeds of their own destruction," Dӧrr said. "Exploring synergies between antibiotics and metabolic perturbations is an emerging field, holding great promise for the development of novel therapies. If we can trigger this internal imbalance, we might develop therapies that bacteria will find much harder to resist."
The Cornell team plans to test whether the same mechanism operates in other disease-causing bacteria and to screen for molecules that enhance sugar-phosphate buildup. The long-term goal is to translate the basic science into antibiotic strategies that can outpace drug resistance.
This work was supported by the National Institutes of Health and the Weill Institute for Cell and Molecular Biology.
Henry C. Smith is the communications specialist for Biological Systems at Cornell Research and Innovation.
