Vancomycin has been one of medicine’s most trusted last-resort antibiotics for decades, but drug-resistant bacteria have increasingly learned how to shrug it off. Now researchers at Cold Spring Harbor Laboratory (CSHL) and Scripps Research say they have found a way to strip that resistance away and hand the old antibiotic back its bite.
In a study published in Nature Communications, a team led by CSHL chemist John Moses and Scripps Research immunologist Howard Hang describes a small molecule, called pghi-4, that restores vancomycin’s ability to kill vancomycin-resistant Enterococcus faecium (VRE) — one of the drug-resistant “superbugs” the World Health Organization and CDC have flagged as a priority threat. VRE and methicillin-resistant Staphylococcus aureus (MRSA) are both part of the same family of hard-to-treat, antibiotic-resistant infections that have made hospital-acquired infections increasingly difficult to manage.
How a single enzyme lets bacteria dodge the drug
Vancomycin normally works by attaching to a specific building block on the bacterial cell wall and blocking the cell from assembling that wall properly, which kills the microbe. Resistant enterococci get around this by remodeling their peptidoglycan — the mesh-like material that makes up the bacterial cell wall — in ways that keep vancomycin from binding effectively.
The researchers zeroed in on secreted antigen A (SagA), an enzyme enterococci rely on to carry out that peptidoglycan remodeling. Using both genetic knockouts and the pharmacological inhibitor pghi-4, the team showed that disabling SagA activity increases the bacteria’s susceptibility to vancomycin, effectively closing the loophole the bacteria had been using to survive treatment. Combined with vancomycin in the lab, pghi-4 restored the antibiotic’s ability to kill resistant E. faecium.
“This discovery came from fundamental chemical research,” Moses said in a statement. “Reaction development led to the discovery of the first inhibitor of an important enzyme involved in antibiotic resistance.”
A two-institution effort with six named funders
The project paired CSHL’s chemistry with Scripps Research’s immunology, and its funding trail is unusually transparent for a basic-science discovery: the work was supported by six separate funders, including the National Institutes of Health, the National Cancer Institute, the Australian Research Council, the Empire State Development/New York State Biodefense Commercialization Fund, the F.M. Kirby Foundation, and the Starr Foundation. That mix of federal science agencies, a state biodefense-commercialization program, and two private philanthropic foundations reflects how much cross-institutional and cross-sector support it can take to move a chemistry-bench finding toward something with real clinical relevance.
Why it matters
Antimicrobial resistance is one of the more persistent threats in infectious disease, and vancomycin-resistant enterococci are among the pathogens clinicians worry about most because treatment options narrow quickly once first-line drugs stop working. Rather than developing an entirely new antibiotic from scratch — a slow, expensive process — this approach pairs a small-molecule inhibitor with a drug that is already approved and well understood, potentially offering a faster path to restoring its usefulness. The findings are still at the research stage; the reported activity was demonstrated against resistant E. faecium in the lab, and further work would be needed before any such combination could be evaluated in patients.
Source
Fam, K.T., et al. “Genetic and pharmacological inactivation of peptidoglycan remodeling increases antibiotic susceptibility of vancomycin-resistant Enterococcus faecium.” Nature Communications, June 16, 2026. DOI: 10.1038/s41467-026-74057-1.
Read the original release from Cold Spring Harbor Laboratory: “A secret weapon against superbugs”.
