Could Antibiotic Adjuvants Make Old Drugs as Good as New?

Antibiotic resistance has quietly become one of the greatest threats to global healthcare. Each year, drug-resistant bacteria claim lives by rendering once-reliable antibiotics ineffective, turning routine surgeries, cancer treatments, and even common infections into potentially life-threatening events.

Scientists around the world are racing to find new ways to stay ahead of these evolving pathogens. The answer may not lie in discovering an entirely new antibiotic, but in reinventing the chemistry behind the ones we already have. That’s the promise of antibiotic adjuvants. Rather than kill bacteria themselves, these partner molecules restore the effectiveness of existing antibiotics.

The approach relies on chemistry research like that of Professor John Moses at Cold Spring Harbor Laboratory (CSHL), where he and his team have spent years developing new chemical reactions that accelerate drug discovery.

Using a methodology known as diversity oriented clicking (DOC), developed in the Moses laboratory, researchers have synthesized a molecular library of more than 150 compounds. This library already underpins discoveries in both antibiotic resistance and cancer research.

In collaboration with Scripps Research, this library has now helped restore the activity of vancomycin, a powerful antibiotic widely used to treat serious infections such as MRSA and Clostridium difficile (C. diff). These well-known pathogens can evolve into antibiotic-resistant “superbugs,” overcoming frontline treatments like vancomycin and spreading rapidly through hospitals, nursing homes, and the wider community.

In their new study, researchers from the Moses lab at CSHL and Professor Howard Hang’s group at Scripps discovered a way to restore the activity of vancomycin by inhibiting a key bacterial enzyme known as secreted antigen A (SagA) with a small molecule called pghi-4. Pghi-4 was originally discovered in the Moses laboratory in 2020. When the team treated drug-resistant E. faecium with the combination of vancomycin and pghi-4, the antibiotic’s ability to kill the bacteria was restored.

For Moses, what makes this discovery particularly exciting is that it didn’t begin with the search for a new antibiotic.

“This discovery came from fundamental chemical research,” he explains. “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 to both keep our library of molecules up to date and add more for collaborators to take advantage of in their research.”

By opening their molecular library for collaborative research, the hope is that similar strategies may one day lead to effective treatments for other superbugs, including drug-resistant strains of tuberculosis.

“This work reflects a philosophy of chemistry that’s designed to accelerate drug discovery in its purest form,” says Moses. “By using reliable, robust, and intelligent chemical reactions, we can build new molecules more efficiently. That’s exactly the approach we used here.”

As antibiotic resistance continues to rise worldwide, the study serves as a reminder that tomorrow’s medical breakthroughs may begin not in a hospital, but rather at a lab bench, where a chemist is simply asking what new molecules are possible.

Reference: Fam KT, Chodisetti PK, Wang Z, et al. Genetic and pharmacological inactivation of peptidoglycan remodeling increases antibiotic susceptibility of vancomycin-resistant Enterococcus faecium. Nat Commun. 2026. doi: 10.1038/s41467-026-74057-1

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