Vancomycin, one of the most powerful antibiotics ever developed, is losing the battle against Enterococcus faecium. The bacterium, which causes hospital-acquired infections that can be fatal in immunocompromised patients, has evolved resistance to vancomycin so consistently that clinicians in many settings consider the drug a last resort that no longer works. The standard response to such resistance is to develop a new antibiotic, a process that takes years and costs billions of dollars with no guarantee of success.
A team at Cold Spring Harbor Laboratory and Scripps Research has published a different approach in Nature Communications. Instead of searching for a new drug, they revived the old one by blocking the enzyme that allows E. faecium to resist it. The strategy, known as chemical rescue, uses a small molecule called pghi-4 to inhibit the bacterial enzyme secreted antigen A (SagA), stripping the bacteria of their resistance and restoring vancomycin’s bactericidal activity.
The logic of chemical rescue
The economics of antibiotic development are notoriously unfavorable. A new antibiotic costs an estimated $1 billion to $2 billion to bring to market, yet the drug must be used sparingly to prevent resistance, which means it generates far less revenue than a chronic disease treatment. As a result, major pharmaceutical companies have largely abandoned antibiotic research, leaving the field to academic labs and small biotech firms.
Chemical rescue sidesteps this problem by working with existing, approved antibiotics. Instead of developing a completely new molecule that kills bacteria through a novel mechanism, researchers develop an adjuvant, a molecule that has little or no antibacterial activity on its own but blocks the bacterial resistance mechanism, allowing the old antibiotic to work again. The adjuvant is co-administered with the antibiotic; the bacteria die from the same drug they had evolved to defeat.
The approach is not new in principle. The combination of amoxicillin and clavulanic acid (Augmentin) uses this same logic: clavulanic acid inhibits bacterial beta-lactamase enzymes, protecting amoxicillin from degradation. But applying the approach to vancomycin resistance required understanding a resistance mechanism that was only recently identified.
The target: SagA
Enterococcus faecium resists vancomycin through a combination of cell wall modifications and biofilm formation. The enzyme SagA (secreted antigen A) plays a central role in both processes. It remodels the bacterial cell wall in a way that reduces vancomycin’s binding affinity, and it contributes to the formation of biofilms, dense bacterial communities that antibiotics cannot easily penetrate.
The pghi-4 molecule, first synthesized in the Moses laboratory at Cold Spring Harbor in 2020, inhibits SagA by binding to its active site and blocking its enzymatic activity. Without a functional SagA, the bacteria cannot maintain their cell wall resistance or build protective biofilms. Vancomycin can then bind to its target, a cell wall precursor molecule, and disrupt cell wall synthesis as it was designed to do.
The discovery was made possible by a chemical synthesis technique called Diversity Oriented Clicking (DOC), developed by John Moses at CSHL. DOC builds large libraries of structurally diverse molecules rapidly, enabling researchers to screen for activity against specific protein targets without having to synthesize each candidate individually. The Moses lab’s library now contains more than 150 compounds that have been used in antibiotic resistance and cancer research.
The evidence
In laboratory cultures, the combination of pghi-4 and vancomycin restored killing activity against drug-resistant E. faecium isolates that had been untreatable with vancomycin alone. The pghi-4 molecule showed no significant antibacterial activity on its own, confirming that it functions specifically as an adjuvant.
The team, led by Moses at CSHL and Howard Hang at Scripps Research, is now exploring whether the same strategy works against other drug-resistant pathogens. Resistant forms of tuberculosis are a candidate target, and the chemical rescue approach is being tested against resistance mechanisms in Gram-negative bacteria, which have outer membranes that make them inherently harder to treat than the Gram-positive E. faecium.
The pipeline problem solved differently
The advantage of chemical rescue is speed. A new antibiotic candidate must go through Phase 1 safety trials, Phase 2 efficacy trials, and large Phase 3 trials before approval, a process that takes at least a decade. An adjuvant for an existing, approved antibiotic can sometimes be tested more efficiently because the safety profile of the antibiotic itself is already well understood. The adjuvant is a new chemical entity, so it requires its own safety data, but the combination therapy can enter Phase 2 trials with a shorter preclinical runway.
“Reaction development led to the discovery of the first inhibitor of an important enzyme involved in antibiotic resistance,” Moses said. “This is a process we are constantly refining to keep our library of molecules up to date.”
The fundamental chemistry that produced pghi-4 continues to yield new candidates. The DOC library is regularly expanded with new reactions, and the Moses lab shares the library with collaborators working on different resistance targets. For each resistance enzyme that can be structurally characterized, there is a potential screening campaign, and a potential adjuvant.
Limitations and unknowns
The pghi-4 molecule has only been tested in vitro. Animal model studies have not yet been reported, and it will be years before the combination can be evaluated in humans. The adjuvant approach also depends on the resistance mechanism being enzymatic and druggable, not all resistance mechanisms can be blocked by a small molecule.
For E. faecium, the emergence of resistance to the combination itself is a theoretical concern, though the probability is lower than for a single drug because vancomycin and pghi-4 target different bacterial processes simultaneously. Combination therapy has historically been more durable than monotherapy for precisely this reason.
The broader lesson, Moses said, is that the antibiotic crisis can be addressed from multiple directions. “A future treatment may begin not with a new antibiotic, but with a carefully designed molecule that helps an old one work again.”
Reference: Fam, K.T. et al. Nature Communications (2026). DOI: 10.1038/s41467-026-74057-1
Sources: Cold Spring Harbor Laboratory press release via ScienceDaily (July 22, 2026).