Researchers at the California Institute of Technology have identified a critical weak point in drug-resistant bacteria, one that multiple unrelated viruses have independently learned to exploit. The findings, published in the February 26 issue of Nature, could guide the development of an entirely new class of antibiotics targeting a protein called MurJ.
The study was led by Yancheng Evelyn Li, a graduate student in the lab of Bil Clemons, Arthur and Marian Hanisch Memorial Professor of Biochemistry at Caltech and the paper’s corresponding author.
A Protein That Bacteria Cannot Live Without
MurJ is one of three proteins, alongside MraY and MurG, that move the building blocks of peptidoglycan across the bacterial inner membrane. Peptidoglycan is the rigid material forming the bacterial cell wall. Without it, bacteria die. If any one of these three proteins stops functioning, the entire construction process halts.
Peptidoglycan exists in bacteria but not in human cells, which makes it an especially attractive drug target. Penicillin and amoxicillin already work by disrupting a later stage of this same pathway. No approved drug, though, directly inhibits MraY, MurG, or MurJ.
What the Viruses Revealed
Bacteriophages, viruses that infect bacteria, face a specific problem: after replicating inside a bacterial cell, they must break through the peptidoglycan layer to escape. Clemons describes the material as acting “like chainmail,” trapping phages that cannot penetrate it.
The Clemons lab found that several distinct phages evolved separate proteins, called Sgl proteins, that all disable MurJ in the same way. High-resolution imaging showed these viral proteins lock MurJ into a fixed outward-facing position, stopping cell wall construction entirely and killing the bacterium.
The fact that unrelated viruses independently arrived at the same solution points to MurJ as a structurally constrained target, one that bacteria cannot easily mutate away without losing essential function.
Why Resistance Makes This Research Urgent
The context for this work is blunt. Clemons states that bacteria resistant to all available medicines now exist, and that tens of thousands of people in the United States alone die each year from antibiotic-resistant infections, with that number rising.
“Evolution is powerful, and in bacteria, resistance to antibiotics develops quickly,” Clemons said. “We need new antibiotics to combat this.”
The discovery matters because it provides a structural template. Knowing precisely how the Sgl proteins freeze MurJ gives chemists a blueprint to design small molecules that replicate the same effect. Clemons notes that small molecules capable of inhibiting these proteins can be found either in nature or synthesized from chemical libraries.
From Viral Strategy to Drug Design
The research reflects a broader shift in antibiotic discovery: looking at what nature has already engineered. Phages have spent billions of years evolving ways to defeat bacterial defenses. Their solutions, encoded in compact genomes with very little room for redundancy, tend to be precise and mechanistically efficient.
The structural detail captured in this study, showing exactly how MurJ gets locked in place, gives drug developers a concrete starting point rather than a theoretical one. Whether that translates into a clinical compound remains a separate challenge, but the target is now mapped with a resolution that did not exist before.
Photo by tian dayong on Unsplash
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