Convergent MurJ flippase inhibition by phage lysis proteins
Nature
by Yancheng E. LiFebruary 26, 2026
AI-Generated Deep Dive Summary
Scientists have uncovered a groundbreaking mechanism by which phage-encoded single-gene lysis proteins (Sgls) inhibit the essential bacterial lipid II flippase MurJ, a key player in cell wall biosynthesis. This discovery highlights a novel pathway for developing antimicrobial drugs to combat antibiotic resistance. Researchers identified that three distinct Sgls—SglM from phage M, SglPP7 from phage PP7, and a newly discovered SglCJ3 from phage Changjiang3—converge on the same mechanism to trap MurJ in an open conformation, effectively blocking its function. This convergence suggests a shared evolutionary strategy to target the same critical interface of MurJ.
The study utilized cryo-EM and structural analysis to reveal how these Sgls bind to MurJ, inducing a periplasm-open state that halts lipid II flipping, a vital step in peptidoglycan synthesis. This mechanism was consistent across all three Sgls, despite their differing evolutionary origins and lack of sequence similarity. The findings also underscore the potential for designing antimicrobial agents that mimic this inhibitory pathway, targeting Gram-negative bacteria where MurJ remains an underexplored but essential drug target.
This research bridges virology and bacteriology, offering fresh insights into bacterial resistance mechanisms and paving the way for innovative therapies. By understanding how these phage proteins interact with MurJ, scientists can develop new strategies to disrupt cell wall synthesis in pathogens, particularly those resistant to conventional antibiotics. This convergence of natural antiviral and antibacterial systems represents a significant leap forward in combating the global crisis of antimicrobial resistance.
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Originally published on Nature on 2/26/2026