Disabling SagA enzyme in VREfm infections makes drug-resistant bacteria vulnerable to vancomycin

In a groundbreaking discovery that offers renewed hope in the fight against antibiotic resistance, scientists at Scripps Research have uncovered a method to restore the effectiveness of vancomycin—a powerful antibiotic—against vancomycin-resistant *Enterococcus faecium* (VREfm). This finding comes amid growing concerns over the rise of drug-resistant infections, which pose a severe threat to public health globally. The study, published in *Nature Communications*, reveals how disabling a specific bacterial enzyme called SagA can render VREfm susceptible to vancomycin once again, potentially offering a novel treatment strategy without the need for entirely new antibiotics.

Vancomycin-resistant *E. faecium* has become a major concern in hospitals due to its ability to resist multiple antibiotics, including vancomycin, which is typically reserved for treating serious infections. Researchers sought to determine whether disrupting SagA, a key enzyme involved in bacterial cell wall remodeling, would make VREfm more vulnerable to vancomycin. By genetically deleting SagA from the bacteria, they observed a marked increase in susceptibility to vancomycin. Senior author Howard Hang explained that SagA plays a crucial role in enabling proper bacterial division, and its disruption weakens the bacteria’s defenses against the antibiotic.

The results showed that while the deletion of SagA did not significantly affect the bacteria’s resistance to other antibiotics like ampicillin, daptomycin, and ceftriaxone, it specifically made them more sensitive to vancomycin. This indicated that the effect was not merely a general weakening of the bacteria but rather a targeted exposure of the site where vancomycin binds. The findings were further validated using a mouse model of sepsis, demonstrating the potential therapeutic relevance of this approach.

To explore non-genetic methods of achieving similar effects, the researchers screened a vast chemical library and identified a class of compounds known as β-chloroalkenyl sulfonyl fluorides. Among these, their lead compound, named pghi-4, demonstrated a remarkable ability to chemically inhibit SagA. When combined with vancomycin, pghi-4 reduced the required dose of the antibiotic by up to eightfold, effectively enhancing its potency against VREfm. This effect was consistent across various clinical isolates and led to a reduction in bacterial load in infected mice.

SagA belongs to a family of enzymes called NlpC/P60 peptidoglycan hydrolases, which have previously eluded successful drug targeting. The ability to pharmacologically inhibit this enzyme family represents a significant advancement in the field. According to Hang, this achievement marks a substantial step forward in developing strategies to combat antibiotic resistance by targeting fundamental aspects of bacterial physiology.

The study introduces a promising category of treatments known as antibiotic adjuvants—compounds that enhance the efficacy of existing antibiotics. While proven adjuvants currently exist for a limited number of drugs, this research presents the first such adjuvant specifically developed for vancomycin. The implications extend beyond VREfm, as the strategy might be applicable to other bacteria harboring additional copies of SagA-like enzymes, particularly since VREfm strains often possess more of these enzymes.

The researchers are now focusing on developing more potent second-generation derivatives that combine the existing compound with vancomycin. They envision extending this approach to other antibiotic-resistant bacteria and their corresponding antibiotics, including pathogens such as tuberculosis and drug-resistant *Staphylococcus aureus*. This discovery underscores the importance of exploring innovative ways to repurpose existing antibiotics, offering a potential solution to the escalating crisis of antibiotic resistance.