Vancomycin is one of medicine’s most important last-resort antibiotics — a drug doctors turn to when nearly everything else has failed. Now researchers at Cold Spring Harbor Laboratory and Scripps Research have found a way to make it work again against the bacteria that had learned to defeat it.
At a glance
- Antibiotic resistance: Drug-resistant bacteria — including MRSA and Clostridium difficile — can evade vancomycin, spreading dangerous infections through hospitals, nursing homes, and communities.
- Antibiotic adjuvant: The team identified a small companion molecule called pghi-4 that disables a key bacterial enzyme, allowing vancomycin to kill resistant E. faecium again in laboratory tests.
- Molecular library: The breakthrough came from a collection of more than 150 compounds built using a technique called diversity oriented clicking, developed in the Moses laboratory at CSHL.
A drug that stopped working
Vancomycin has long been a cornerstone of treatment for severe bacterial infections. Doctors rely on it for MRSA and Clostridium difficile — two pathogens notorious for resisting frontline antibiotics and causing serious harm in healthcare settings. But bacteria evolve, and some strains have developed the ability to shrug off vancomycin too.
When that happens, clinicians have very few options. The pipeline of entirely new antibiotics is thin, and developing one from scratch takes years and enormous resources. That reality has pushed researchers to ask a different question: instead of finding a new drug, what if you could fix an old one?
That’s the logic behind antibiotic adjuvants — molecules that don’t kill bacteria on their own but remove the defenses bacteria use to neutralize existing antibiotics. Think of it less as a new weapon and more as a way to restore the ones medicine already has.
How the discovery happened
Professor John Moses and his team at Cold Spring Harbor Laboratory have spent years building a library of chemical compounds using a technique the lab created called diversity oriented clicking. The method is designed to make drug discovery faster and more systematic — building a wide variety of molecules efficiently so other researchers can screen them for useful properties.
One molecule in that library, pghi-4, was first identified in the Moses laboratory in 2020 C.E. It targets a bacterial enzyme called secreted antigen A, or SagA — a protein that helps some bacteria maintain resistance to antibiotics like vancomycin.
In a collaboration with Professor Howard Hang’s team at Scripps Research, scientists tested what happened when drug-resistant Enterococcus faecium was treated with both vancomycin and pghi-4 together. The antibiotic regained its ability to kill the bacteria. The findings were published in Nature Communications on June 16, 2026 C.E.
“This discovery came from fundamental chemical research,” Moses said. “Reaction development led to the discovery of the first inhibitor of an important enzyme involved in antibiotic resistance. This is a process we’re constantly refining.”
Why this approach matters beyond vancomycin
The finding is significant in itself, but the broader strategy may be more important than any single result. By maintaining the molecular library and making it available to collaborators, the CSHL team is building infrastructure for a faster kind of drug discovery — one that could apply to other resistant infections, including drug-resistant tuberculosis.
“This work reflects a philosophy of chemistry that’s designed to accelerate drug discovery in its purest form,” Moses said. “By using reliable, robust, and intelligent chemical reactions, we can build new molecules more efficiently. That’s exactly the approach we used here.”
It also illustrates a point worth holding onto: some of the most consequential medical advances don’t arrive as entirely new discoveries. They come from rethinking chemistry that already exists. This is part of a wider set of public health wins that researchers around the world are building — not always through radical invention, but through careful, cumulative science.
What remains to be done
The results so far are from laboratory experiments, not human trials. pghi-4 has shown it can restore vancomycin’s effectiveness against resistant bacteria in controlled settings, but translating that into a safe and effective clinical treatment involves years of additional testing. It’s also worth noting that the SagA enzyme targeted here is relevant to specific resistant strains — not all forms of antibiotic resistance use the same mechanism, so this approach won’t be a universal fix.
Antibiotic resistance remains one of the most complex and urgent problems in global health, driven in part by overuse and misuse of antibiotics across human medicine and agriculture. No single discovery resolves it. But each credible advance — each way researchers find to extend the useful life of drugs that already exist — buys time and narrows the gap between what bacteria can do and what medicine can answer.
The research was funded by the National Institutes of Health, the National Cancer Institute, and other organizations.
Read more
For more on this story, see: Science Daily
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