Disabling the enzyme doesn't just weaken the bacteria—it exposes where vancomycin kills.
For decades, vancomycin has stood as one of medicine's last defenses against the most dangerous bacterial infections — yet resistance has steadily eroded its power, contributing to nearly five million deaths each year. Scientists at Scripps Research have now identified a way to restore that power, not by creating a new antibiotic, but by disabling a bacterial enzyme called SagA that allows resistant strains to evade the drug. A chemical compound, pghi-4, can pharmacologically silence this enzyme, reducing the vancomycin dose needed to kill resistant bacteria by as much as eightfold. In a time when bacteria evolve faster than medicine can answer, the wisdom of reviving what we already have may prove as vital as any new discovery.
- Antibiotic-resistant bacteria now kill an estimated 4.7 million people annually, and vancomycin — one of the last drugs doctors can reach for — is losing ground in hospitals worldwide.
- Vancomycin-resistant Enterococcus faecium has learned to remodel its own cell wall using an enzyme called SagA, effectively locking vancomycin out of the very site it needs to destroy.
- Scripps Research scientists found that genetically disabling SagA made resistant bacteria strikingly vulnerable to vancomycin again — and crucially, only to vancomycin, confirming the mechanism was precise rather than a general weakening.
- A chemical compound called pghi-4 can pharmacologically silence SagA without genetic editing, cutting the effective vancomycin dose by up to eightfold across multiple real-patient bacterial strains and in mouse models of sepsis.
- This marks the first antibiotic adjuvant ever developed for vancomycin, and opens a new front against resistance by targeting an entire family of cell-wall enzymes that no drug had previously reached.
Every year, bacteria that no longer respond to our strongest medicines claim millions of lives — 4.7 million in 2019 alone. The problem compounds as bacteria evolve faster than new drugs can be developed, and the roster of true last-resort treatments grows shorter. Into this crisis, researchers at Scripps Research have introduced a different kind of answer: not a new antibiotic, but a way to make an old one work again.
The target is vancomycin-resistant Enterococcus faecium, or VREfm — a hospital-acquired pathogen that has learned to deflect vancomycin, a drug normally reserved for life-threatening infections. The Scripps team focused on an enzyme called SagA, which remodels the bacterial cell wall and allows the microorganism to divide and spread. When they genetically deleted SagA from resistant bacteria, something unexpected happened: the bacteria became markedly vulnerable to vancomycin again. Critically, the effect was specific — deleting SagA did not make the bacteria more susceptible to other antibiotics like ampicillin or daptomycin, suggesting the deletion was exposing the precise site where vancomycin acts, rather than simply weakening the bacteria overall. The strategy also proved effective in mouse models of sepsis.
Genetic deletion, of course, cannot be administered to patients. So the team screened a large chemical library and identified a class of compounds capable of pharmacologically disabling SagA. Their lead candidate, pghi-4, reduced the vancomycin dose needed to kill VREfm by up to eightfold, and the effect held across multiple clinical strains collected from real patients.
The significance runs deeper than a single compound. SagA belongs to a family of cell-wall-remodeling enzymes — NlpC/P60 peptidoglycan hydrolases — that no drug had ever successfully targeted before. This makes pghi-4 the first antibiotic adjuvant ever developed for vancomycin, and potentially a template for addressing other resistant strains that carry multiple SagA-like enzymes. Published in Nature Communications in June 2026, the research suggests that in the long struggle against resistance, the art of reviving what medicine already possesses may matter as much as the search for something entirely new.
Every year, bacteria that no longer respond to our strongest medicines kill millions of people. In 2019 alone, antibiotic-resistant infections were linked to 4.7 million deaths worldwide. The problem keeps worsening as bacteria evolve faster than we can develop new drugs, and the arsenal of truly last-resort treatments grows thinner. Now researchers at Scripps Research have found a way to bring one of those critical weapons back to life.
The bacteria in question is vancomycin-resistant Enterococcus faecium, or VREfm—a hospital-acquired infection that has learned to shrug off vancomycin, a potent antibiotic normally reserved for life-threatening cases. The infection is becoming more common in hospital settings, and it can resist multiple antibiotics held in reserve for the toughest infections. The Scripps team wondered whether they could make VREfm vulnerable to vancomycin again by disabling a specific enzyme the bacteria uses to survive.
That enzyme is called secreted antigen A, or SagA. It works by remodeling the bacterial cell wall, allowing the microorganism to divide and spread. The researchers genetically deleted SagA from VREfm samples and found that without it, the bacteria became markedly more susceptible to vancomycin. Howard Hang, the senior author and a professor at Scripps Research, explained that disrupting the enzyme prevents bacteria from dividing properly, which in turn makes them sensitive to the antibiotic they had previously resisted. The finding was surprising: previous work had shown that deleting SagA made bacteria frailer in general, but nobody expected it would specifically restore vancomycin's killing power against already-resistant strains.
To confirm the effect was specific to vancomycin, the researchers tested whether deleting SagA made the bacteria more vulnerable to other antibiotics like ampicillin, daptomycin, and ceftriaxone. It did not. This suggested the deletion wasn't simply weakening the bacteria overall, but was instead exposing the precise spot where vancomycin binds and destroys the cell wall. The strategy also worked in mouse models of sepsis, a life-threatening blood infection.
But genetic deletion is not a practical treatment. So the team screened a large chemical library and found a class of compounds called β-chloroalkenyl sulfonyl fluorides that could chemically disable SagA without altering the bacteria's genes. Their lead compound, called pghi-4, proved especially promising. When combined with vancomycin, pghi-4 reduced the amount of antibiotic needed to kill VREfm by up to eightfold. The effect held across multiple clinical isolates—different strains collected from real patients—and reduced bacterial burden in infected mice.
What makes this discovery significant is that SagA belongs to a family of cell-wall-remodeling enzymes called NlpC/P60 peptidoglycan hydrolases that no drug had ever successfully targeted before. Hang called demonstrating that this enzyme family could be pharmacologically targeted a major step forward. The approach falls into a category of treatments known as antibiotic adjuvants: compounds that are not themselves antibiotics but help existing antibiotics work better against resistant bacteria. A few proven adjuvants already exist for a narrow range of drugs, but this is the first such helper developed for vancomycin, one of medicine's most important last-resort treatments.
The research, published in Nature Communications on June 16, 2026, suggests that pghi-4 and related compounds may target other peptidoglycan-remodeling enzymes beyond SagA. That possibility matters because VREfm strains tend to carry extra copies of SagA-like enzymes, meaning bacteria with multiple copies could be even more vulnerable to this approach. As antibiotic resistance continues to outpace the development of new drugs, strategies that revive old ones may prove as important as discovering entirely new ones.
Citas Notables
If you disrupt that, the bacteria don't divide as well, and it makes the bacteria more sensitive to vancomycin.— Howard Hang, senior author and professor at Scripps Research
To demonstrate you can pharmacologically target this enzyme family is a big step forward.— Howard Hang
La Conversación del Hearth Otra perspectiva de la historia
Why does disabling one enzyme specifically restore vancomycin's power when the bacteria have already evolved resistance?
Because SagA does something very specific—it remodels the cell wall in a way that lets vancomycin's binding site stay hidden. When you remove the enzyme, that site becomes exposed again. The bacteria didn't evolve a new wall; they evolved a way to keep vancomycin from reaching the vulnerable spot.
So you're not killing the bacteria with a new drug. You're just making the old drug work again.
Exactly. And that matters enormously because developing a truly new antibiotic takes years and billions of dollars. If you can resurrect one that already exists, you've bought time and resources.
The compound pghi-4 reduces the vancomycin dose by eightfold. Does that mean patients would take less medicine?
Potentially, yes. Less drug means fewer side effects, lower costs, and less selective pressure on other bacteria in the body. But this is still early work. It worked in mice. Human trials would come much later.
What happens if bacteria evolve resistance to pghi-4 itself?
That's the real question nobody can answer yet. But the enzyme family SagA belongs to is ancient and fundamental to how bacteria build their walls. It's harder to abandon than some other targets, which might make resistance slower to develop.
Is this the beginning of a new strategy, or a one-off win?
It's the beginning. The researchers showed you can target an entire family of enzymes that nobody had successfully drugged before. If pghi-4 works in humans, the same approach could work against other resistant bacteria that use similar enzymes.