Why This Matters
Antibiotic resistance is one of the most serious threats facing modern medicine. When bacteria develop the ability to defeat the antibiotics held in reserve for the toughest infections, the consequences are measured in lives. Vancomycin-resistant Enterococcus, or VRE, is one of the most dangerous examples: a bacterium that can resist not just vancomycin but multiple antibiotics simultaneously, spreading through hospitals and health care facilities and disproportionately affecting patients who are already critically ill.
Developing a new antibiotic from scratch typically takes more than a decade and billions of dollars. Researchers at Cold Spring Harbor Laboratory (CSHL) and Scripps Research have taken a different approach — and published findings on July 22, 2026, showing it may work.
Instead of creating a new drug, they restored an old one.
What We Know So Far
The key findings were summarized in a CSHL press release on July 22, 2026, based on research published in Nature Communications on June 16, 2026. Scientists at the Moses Laboratory at CSHL and Professor Howard Hang's group at Scripps Research identified a way to make vancomycin effective again against drug-resistant VRE by targeting a bacterial enzyme called secreted antigen A, or SagA.
SagA is an enzyme that VRE uses to remodel its cell wall, a process that makes the bacteria more robust and better able to withstand antibiotic attack. By blocking SagA using a small molecule called pghi-4, the researchers were able to disrupt the bacteria's defenses and restore vancomycin's ability to kill it.
When drug-resistant Enterococcus faecium was treated with the combination of vancomycin and pghi-4, the antibiotic's killing ability was restored. The pghi-4 compound reduced the amount of vancomycin needed to kill VREfm by up to 8-fold in laboratory tests. The effect held up across multiple clinical isolates, and it reduced the bacterial burden in infected mice, according to the EurekAlert press release.
Where the Threat Is Highest
VRE is primarily a hospital-acquired infection, meaning it is most commonly found in patients who are already being treated in health care settings. The bacteria spread easily on the hands of health care workers and on surfaces in clinical environments, and they disproportionately affect patients with weakened immune systems, people who have been on long courses of antibiotics, and people with catheters or other invasive medical devices.
Patients in intensive care units, those undergoing cancer treatment or organ transplantation, and people who have had recent surgeries or prolonged hospitalizations face the highest risk of VRE infection. The bacteria are also a significant concern in long-term care facilities, where elderly residents with multiple underlying conditions and frequent antibiotic exposures create conditions favorable for resistant bacteria to spread.
The broader context: VRE and similar drug-resistant bacteria collectively contribute to tens of thousands of deaths annually in U.S. health care settings. Antibiotic resistance was linked to an estimated 4.7 million deaths worldwide in 2019 alone, according to Scripps Research scientists.
What Doctors and Experts Say
Professor Howard Hang at Scripps Research described the significance of the finding in terms of what it demonstrates about bacterial biology: "To demonstrate you can pharmacologically target this enzyme family is a big step forward."
SagA belongs to a family of cell-wall-remodeling enzymes called NlpC/P60 peptidoglycan hydrolases. No drug had ever successfully targeted this enzyme family before this research. The identification of pghi-4 as the first-in-class inhibitor of these enzymes opens a new category of potential adjuvant treatments, meaning compounds designed not to kill bacteria directly but to strip them of specific defenses so that existing antibiotics can do their job.
Professor Joshua Moses at CSHL, in whose laboratory pghi-4 was first discovered in 2020, noted the unusual origin of the finding: "This discovery came from fundamental chemical research. 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."
The approach belongs to a growing category of treatments known as antibiotic adjuvants: compounds paired with existing antibiotics to overcome specific resistance mechanisms, rather than new antibiotics that must pass the full regulatory approval process on their own.
What the Evidence Shows and What It Does Not
The current evidence is preclinical. The pghi-4 findings come from laboratory experiments using bacterial cultures (ex vivo) and a mouse infection model. There are no human safety or efficacy data for pghi-4 as a treatment for VRE infections.
The researchers are already developing more potent second-generation derivatives of pghi-4 and working toward combinations that couple the compound directly with vancomycin. They believe the approach could eventually extend to other resistant bacteria and antibiotic combinations.
MedicalDaily Evidence Check
- Study type: Preclinical research; laboratory (ex vivo) and mouse model
- Institution: Cold Spring Harbor Laboratory (Moses Lab) and Scripps Research (Hang Lab)
- Published in: Nature Communications, June 16, 2026; CSHL press release July 22, 2026
- What it found: pghi-4 inhibits the SagA enzyme in VRE, restoring vancomycin's killing ability up to 8-fold in culture; reduced bacterial burden in infected mice
- What it did not prove: That pghi-4 is safe or effective in humans; no clinical trial data exist; human testing has not begun
- What readers should know: This is promising early-stage science. Patients currently being treated for VRE should follow their physicians' guidance on available approved antibiotics. pghi-4 is not available as a treatment.
Who Faces the Greatest Risk?
Patients most at risk of serious VRE infection include:
- ICU patients with prolonged stays and multiple invasive procedures
- Recipients of organ transplants, who take immunosuppressive medications that reduce the immune system's ability to fight infection
- Cancer patients undergoing chemotherapy, particularly those with prolonged neutropenia (low white blood cell count)
- People with urinary catheters or central venous catheters in health care settings
- Residents of long-term care facilities, particularly those who have received multiple antibiotic courses
- Patients who have had abdominal surgery, particularly colorectal procedures
Healthy adults in the community who have not been hospitalized recently face very low risk of VRE infection.
Symptoms and Warning Signs to Watch For
VRE does not always cause symptoms. In hospitalized patients, VRE can cause infections in a range of sites, including:
- Urinary tract infections: burning on urination, frequent urination, pelvic or flank pain, fever
- Wound infections: redness, warmth, swelling, or discharge at a surgical or wound site
- Bloodstream infections (bacteremia): fever, chills, low blood pressure, rapid heart rate, and confusion — a presentation that may indicate sepsis and requires urgent evaluation
- Endocarditis (heart valve infection): fatigue, fever, new heart murmur, joint pain
Patients in health care settings who develop any of these symptoms should alert their care team immediately. Diagnostic cultures will be needed to determine whether VRE is involved and which antibiotics, if any, remain effective.
What You Can Do Now
- If you are a patient being treated for a VRE infection, ask your physician which antibiotics are currently being used and whether susceptibility testing has confirmed that your specific strain is sensitive to those drugs.
- Practice rigorous hand hygiene in health care settings. Alcohol-based hand sanitizers and soap-and-water handwashing are both effective at reducing VRE transmission. Proper hand hygiene from health care workers, visitors, and patients themselves is the single most important infection control measure.
- If you are scheduled for an elective surgery or procedure, ask whether your hospital screens patients for VRE before admission. Many hospitals have implemented pre-admission screening programs for high-risk patients.
- Do not take antibiotics for viral infections. Unnecessary antibiotic use accelerates the development of resistance in the bacteria that colonize and can infect the human body.
Cost and Access: What Patients Should Know
Treatment for confirmed VRE infections currently relies on a limited set of approved antibiotics, including linezolid and daptomycin, both of which are expensive and have their own resistance risks. These medications are typically available in hospital settings for confirmed infections, with coverage under most insurance plans for patients with documented VRE.
The development of pghi-4 as a clinical compound would require years of additional research, safety testing in humans, and regulatory review before it could reach patients. The researchers have not announced a clinical development partner or commercialization timeline as of this writing.
For health care facilities, infection control remains the most cost-effective intervention: standard contact precautions, active surveillance cultures in high-risk units, and antimicrobial stewardship programs that reduce unnecessary broad-spectrum antibiotic use. The CDC's infection prevention resources include guidelines for VRE management in health care settings.
What Happens Next
The research team is already pursuing second-generation versions of pghi-4 with greater potency, and exploring whether the same SagA-blocking approach can be extended to other resistant bacterial species and antibiotic combinations, including pathogens such as drug-resistant Staphylococcus aureus.
If second-generation compounds perform well in further preclinical testing, the next step would be an Investigational New Drug application with the FDA, followed by Phase 1 safety trials in humans. Given the novelty of the SagA enzyme family as a drug target, that process is expected to take several years.
The CDC's National Antimicrobial Resistance Monitoring System tracks VRE and other resistant bacteria in health care settings and publishes annual reports on resistance trends.
The Bottom Line
Researchers at Cold Spring Harbor Laboratory and Scripps Research have found a promising approach to defeating one of the most dangerous drug-resistant bacteria in U.S. hospitals: by blocking the bacterial enzyme that helps VRE defend itself, they can restore vancomycin's killing power in laboratory and mouse models. The science is early-stage and years from clinical use, but it addresses a genuine and growing public health problem through a mechanism that is entirely new. For patients, health care workers, and anyone who has ever worried about a family member developing an untreatable hospital infection, this is exactly the kind of research the medical community needs to be doing.
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