Researchers restore vancomycin effectiveness against resistant Enterococcus using enzyme inhibitor

Researchers have identified a way to restore the effectiveness of vancomycin, a last-resort antibiotic, against vancomycin-resistant Enterococcus faecium (VREfm), a common cause of healthcare-associated infections. By combining vancomycin with a small-molecule inhibitor of the bacterial enzyme secreted antigen A (SagA), the team made resistant bacteria susceptible again, according to a study published in Nature Communications.

VREfm strains often carry resistance genes that render vancomycin ineffective, contributing to difficult-to-treat infections in hospitals and nursing homes. SagA is a highly conserved NlpC/P60 peptidoglycan hydrolase that remodels the bacterial cell wall, enabling proper division and growth. Genetic deletion of the sagA gene impaired peptidoglycan remodeling, reduced cell separation, and increased vancomycin susceptibility even in strains retaining vanA resistance genes, as detailed in the paper (Nature Communications).

To achieve pharmacological inactivation, scientists from Professor John Moses’s laboratory at Cold Spring Harbor Laboratory (CSHL) and Professor Howard Hang’s group at Scripps Research screened a library of compounds generated via diversity-oriented clicking (DOC) chemistry. They identified first-in-class covalent inhibitors, β-chloro alkenyl sulfonyl fluorides, that target the active-site cysteine of SagA. The lead compound, pghi-4 (originally discovered in the Moses lab in 2020), lowered the minimum inhibitory concentration (MIC) of vancomycin by up to eightfold in a concentration-dependent manner across multiple genetically distinct clinical VREfm isolates (News-Medical; CSHL).

In cellular models, the combination of pghi-4 and vancomycin reduced VREfm infection of murine and human monocytes in a dose-dependent fashion, without significant cytotoxicity from the inhibitor alone. In a mouse model of VREfm-induced sepsis, a two-dose regimen of the combination significantly reduced weight loss and bacterial burden in the spleen and liver compared with either agent alone or vehicle control, the study reported (PMC).

“This discovery came from fundamental chemical research,” Moses said in a CSHL release. “Reaction development led to the discovery of the first inhibitor of an important enzyme involved in antibiotic resistance.” Hang noted that disrupting SagA makes bacteria more sensitive to vancomycin specifically, rather than broadly weakening them against other antibiotics such as ampicillin or daptomycin (EurekAlert; News-Medical).

The work positions peptidoglycan hydrolases as druggable targets and pghi-4-type molecules as antibiotic adjuvants—compounds that do not kill bacteria directly but restore existing drugs. The researchers suggest the strategy could extend to other resistant pathogens, and they are developing more potent derivatives, including potential conjugates with vancomycin. Funding included support from the National Institutes of Health, National Cancer Institute, and other sources (ScienceDaily).

The findings address a key aspect of antimicrobial resistance by reviving an established antibiotic rather than requiring an entirely new one.