LA JOLLA, CA—Antibiotic resistance is one of the most urgent threats to global health, linked to an estimated 4.7 million deaths worldwide in 2019 alone. As more bacteria evolve to evade even last-resort drugs, the supply of effective treatments is shrinking. Now, scientists at Scripps Research have discovered a way to restore the effect of one of those critical antibiotics by disabling a key bacterial enzyme.
The study, published in Nature Communications on June 16, 2026, focused on vancomycin-resistant Enterococcus faecium, or VREfm, a hospital-acquired infection that is becoming increasingly common. VREfm can resist multiple antibiotics held in reserve for the toughest infections, including its namesake, vancomycin, a potent drug often used to treat life-threatening infections.
The researchers wanted to know whether disabling a specific bacterial enzyme called secreted antigen A (SagA) could make VREfm vulnerable to vancomycin again, rendering it treatable without needing a new antibiotic. SagA is found across a wide range of VRE strains, making it an attractive target for therapies designed to work broadly against resistant infections.
When the researchers genetically deleted the enzyme from VREfm, the bacteria became markedly more susceptible to vancomycin.
"The SagA enzyme remodels the cell wall so that bacteria divide properly," says senior author Howard Hang , a professor at Scripps Research. "If you disrupt that, the bacteria don't divide as well, and it makes the bacteria more sensitive to vancomycin."
There was already evidence that genetic deletion of the enzyme makes the bacteria more vulnerable to antibiotics, says Hang. "But the fact that it sensitizes the cells to vancomycin, when the bacteria are already resistant to it, was a surprise."
Deleting SagA had little impact on the bacteria's resistance to other antibiotics such as ampicillin, daptomycin and ceftriaxone. This suggested that the deletion wasn't just making the bacteria frailer overall, but was specifically exposing the site where vancomycin binds. The strategy also worked in a mouse model of sepsis.
The researchers also screened a large chemical library and identified a class of compounds called β-chloroalkenyl sulfonyl fluorides that chemically disable SagA. Their lead compound, called pghi-4, reduced the amount of vancomycin needed to kill VREfm by up to 8-fold when the two were combined. The effect held up across multiple clinical isolates and reduced the bacterial burden in infected mice.
SagA belongs to a family of cell-wall-remodeling enzymes called NlpC/P60 peptidoglycan hydrolases that no drug had ever successfully targeted before. "To demonstrate you can pharmacologically target this enzyme family is a big step forward," says Hang.
The approach is part of a promising category of treatments known as antibiotic adjuvants: compounds that aren't antibiotics themselves but help existing antibiotics work better against resistant bacteria. Proven adjuvants already exist for a narrow range of drugs, but this is the first such helper developed for vancomycin.
The study data suggest that pghi-4 and related compounds may target other peptidoglycan-remodeling enzymes beyond SagA. That raises the possibility that bacteria carrying extra copies of SagA-like enzymes could be more vulnerable to this approach, which is significant because VREfm strains tend to carry more of these enzymes.
"This is a promising new weapon in the ongoing arms race against antibiotic resistance," says Hang. The broader lesson, he adds, is that targeting basic aspects of bacterial physiology can overcome antibiotic resistance. The researchers are already working on more potent second-generation derivatives that couple the existing compound with vancomycin. They believe the same strategy could eventually be extended to other combinations of resistant bacteria and antibiotics, including pathogens such as tuberculosis and drug-resistant Staphylococcus aureus.
In addition to Hang, authors of the study " Genetic and pharmacological inactivation of peptidoglycan remodeling increases antibiotic susceptibility of vancomycin-resistant Enterococcus faecium " include Kyong T. Fam, Pavan Kumar Chodisetti, Adrianna M. Turner, Seiya Kitamura, Benjamin Silva, Yijun Xiong, Althea Hansel-Harris, Matthew Holcomb, Simeon Babarinde, Ian A. Wilson, Stefano Forli, Benjamin F. Cravatt, Donghyun Park, and Dennis W. Wolan of Scripps Research; Zifei Wang, Joshua A. Homer, and John E. Moses of Cold Spring Harbor Laboratory; Christopher J. Smedley of La Trobe University; and Daria Van Tyne of the University of Pittsburgh School of Medicine.
This work was supported by the National Institutes of Health (grant R21AT012958) and Scripps Research start-up funds, with additional support from the Cold Spring Harbor Laboratory NCI Cancer Center Support Grant (5P30CA045508), the Australian Research Council (FT170100156), and the F.M. Kirby Foundation.
