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Convergent MurJ flippase inhibition by phage lysis proteins

Article

Published: 25 February 2026

Convergent MurJ flippase inhibition by phage lysis proteins

Yancheng E. Li

(李妍成)
orcid.org/0000-0002-7110-24481,

S. Francesca Antillon2,3,
Grace F. Baron

orcid.org/0009-0008-3396-31171,

Karthik Chamakura

orcid.org/0000-0002-6196-85712,3,

Ry Young2,3 &
…
William M. Clemons Jr

orcid.org/0000-0002-0021-889X1,4

Nature

(2026)Cite this article

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Subjects

Antibiotics
Cryoelectron microscopy

Abstract

Antimicrobial drug resistance poses a global health challenge that necessitates the identification of new druggable targets1,2,3. The essential lipid II flippase MurJ is a promising yet underexplored antimicrobial target in bacterial cell wall biosynthesis4,5,6,7. The only known inhibitors of Gram-negative (diderm) MurJ are the single-gene lysis proteins (Sgls) from the lytic single-strand RNA phages M (SglM) and PP7 (SglPP7)8,9. SglM and SglPP7 have distinct evolutionary origins and share no sequence similarity. Here we describe a common mechanism of MurJ inhibition by these phage-encoded Sgls. We determined the structures of MurJ-bound SglM and SglPP7 and discovered a third distinct MurJ-targeting Sgl from the predicted phage Changjiang3 (SglCJ3) that we also characterized structurally. Our findings demonstrate that all three Sgls evolved convergently to trap MurJ in a periplasm-open conformation through a common MurJ interface, revealing a pathway for drug design.

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Fig. 1: Structure of the SglM–EcMurJ complex.

Fig. 2: Structure of the SglPP7–EcMurJ complex.

Fig. 3: Discovery of SglCJ3 and structure of the SglCJ3–EcMurJ complex.

Fig. 4: Comparison of Sgl-bound MurJ structures.

Convergent MurJ flippase inhibition by phage lysis proteins