CSHL revives vancomycin against superbugs with resistance-blocking molecule
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Scientists at Cold Spring Harbor Laboratory (CSHL) and Scripps Research have revived the antibiotic vancomycin against drug-resistant E. faecium by pairing it with a small molecule called pghi-4. The combination restored vancomycin's ability to kill the bacteria, offering a strategy to rescue other failing antibiotics without creating entirely new drugs.
The Adjuvant Strategy
Instead of inventing a new antibiotic, researchers used an adjuvant approach: a companion molecule that does not kill bacteria directly but restores the power of existing drugs. The team targeted a bacterial enzyme called secreted antigen A (SagA) using pghi-4, a small molecule first discovered in the Moses laboratory in 2020. When drug-resistant E. faecium was treated with both vancomycin and pghi-4, the antibiotic regained its ability to kill the bacteria.
Diversity Oriented Clicking
Professor John Moses and his team at CSHL developed a technique called diversity oriented clicking (DOC) to build a library of more than 150 compounds. Molecules from this collection have contributed to research on antibiotic resistance and cancer. The collaboration with Scripps Research used the library to identify pghi-4 as the key molecule for restoring vancomycin efficacy.
Implications for Drug Discovery
The finding highlights that the research did not begin as a direct search for a new antibiotic, but rather as a broader effort to speed drug discovery. Vancomycin is commonly used against severe infections including MRSA and C. diff, both of which can develop resistance. The success with pghi-4 raises hopes that similar chemical helpers could rescue other failing medicines.
What's Next
The team plans to test the vancomycin-pghi-4 combination in animal models to assess its safety and efficacy in vivo. It remains unclear whether the approach can be scaled to other antibiotic-adjuvant pairs or whether bacteria will eventually evolve resistance to the adjuvant itself.
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CSHL revives vancomycin against superbugs with resistance-blocking molecule
