Antibiotic resistance is becoming one of the most serious dangers facing modern medicine. As bacteria evolve, drugs that were once reliably effective may no longer be effective. This can make common infections more difficult to treat and increase the risks associated with routine surgeries, cancer treatments, and other medical procedures.
Researchers around the world are looking for ways to stay ahead of these rapidly changing microorganisms. One promising strategy is to make existing drugs work again, rather than inventing entirely new antibiotics. This is the idea behind antibiotic adjuvants, companion molecules that restore the power of antibiotics rather than directly killing bacteria.
Building new molecules to accelerate drug discovery
Professor John Moses and his team at Cold Spring Harbor Laboratory (CSHL) have spent years developing chemical reactions that can make the drug discovery process faster and more efficient.
The researchers are using a technique created in Moses’ lab called diversity-oriented clicking (DOC). Using this method, they built a library containing more than 150 different compounds. Molecules from this collection have already contributed to research into both antibiotic resistance and cancer.
Now, through a collaboration with Scripps Research, this library has helped scientists restore the effectiveness of vancomycin. This powerful antibiotic is effective against MRSA and clostridium difficile (temperature difference). Both pathogens have the potential to develop resistance and become “superbugs” that evade front-line drugs such as vancomycin. The infection can then spread through hospitals, nursing homes, and the community.
Vancomycin recovery against resistant bacteria
In the new study, scientists in CSHL’s Moses lab collaborated with Professor Howard Han’s team at Scripps to identify a way to make vancomycin effective again.
The researchers targeted a bacterial enzyme called secreted antigen A (SagA). They blocked the enzyme using a small molecule known as pghi-4, which was first discovered in Moses’ lab in 2020.
If you have drug resistance E. Feces When treated with both vancomycin and pghi-4, the antibiotic regained its ability to kill the bacteria.
For Moses, one of the most remarkable parts of this discovery is that the research did not begin as a direct search for new antibiotics.
“This discovery arose from basic chemical research,” he explains. “Reaction development led to the discovery of the first inhibitors of key enzymes involved in antibiotic resistance. This is a process we are constantly refining to keep our molecular library up-to-date and add molecules available to our collaborators for research.”
Broad strategy against superbugs
By making this molecular library available to other researchers, the research team hopes that similar approaches may eventually lead to treatments for additional drug-resistant infections. These may include resistant forms of tuberculosis.
“This work reflects a chemistry philosophy aimed at accelerating drug discovery in its purest form,” says Moses. “By using reliable, robust, and intelligent chemical reactions, we can build new molecules more efficiently, and that’s exactly the approach we used here.”
As antibiotic resistance increases around the world, the findings show that important medical advances could come from rethinking the chemistry of existing drugs. Future treatments may start not with new antibiotics, but with carefully designed molecules that help old antibiotics work again.
funding
National Institutes of Health, National Cancer Institute, Australian Research Council, New York State Biodefense Commercialization Fund, FM Kirby Foundation, Starr Foundation
