Researchers at Caltech have discovered how viruses infect bacteria by disabling a key protein called MurJ, essential for cell wall construction. This mechanism, revealed through high-resolution imaging, suggests a new approach to combating antibiotic-resistant superbugs. The findings highlight convergent evolution in unrelated viruses blocking MurJ similarly.
Antibiotic resistance poses a growing threat, with bacteria evolving rapidly against existing treatments. In the United States alone, tens of thousands die annually from such infections, a number increasing steadily. As Bil Clemons, Arthur and Marian Hanisch Memorial Professor of Biochemistry at Caltech, explains, "Evolution is powerful, and in bacteria, resistance to antibiotics develops quickly. This means that we now deal with bacteria that are resistant to all the medicines that we have."
Scientists have long targeted the peptidoglycan biosynthesis pathway, unique to bacteria and absent in human cells. Clemons notes, "Peptidoglycan is a unique feature of bacteria, and that makes it an attractive antibiotic target." Key proteins in this pathway include MraY, MurG, and MurJ, which transport building blocks across the bacterial membrane. While antibiotics like penicillin disrupt later stages, no approved drugs directly inhibit these three proteins yet.
Bacteriophages, viruses that infect bacteria, offer insights. To escape host cells, phages must breach the peptidoglycan layer. The Clemons lab studied small phages using single-gene lysis proteins (Sgls). Earlier work identified SglM and SglPP7 blocking MurJ, a flippase that moves peptidoglycan precursors.
Using cryo-electron microscopy, Yancheng Evelyn Li visualized how these Sgls bind to a groove in MurJ, locking it in an outward-facing conformation and halting transport. Li states, "It is clear that both of these Sgls bind to MurJ in an outward-facing conformation, locking it into this position." This exposed form could aid drug access.
Remarkably, analysis of another phage genome revealed SglCJ3, which inhibits MurJ identically despite no evolutionary relation—a case of convergent evolution. Clemons says, "These peptides, which have no evolutionary links to each other, have both figured out how to target MurJ in a very similar way. We were surprised!" The team, including Li, Grace F. Baron, and collaborators from Texas A&M, published these results in the February 26, 2026, issue of Nature, titled "Convergent MurJ flippase inhibition by phage lysis proteins." Funding came from the Chan Zuckerberg Initiative, National Institutes of Health, and others.
This work underscores phages' potential to inspire new antibiotics by exploiting bacterial vulnerabilities.
