Grace Baron

Keywords cell wall peptidoglycan lipid II lipid transport antibiotics lipid flippase antibiotic target Abbreviations PG (peptidoglycan) MOP (multidrug/oligosaccharidyl-lipid/polysaccharide) TM (transmembrane helix) TaMurJ (Thermosipho africanus MurJ) EcMurJ (Escherichia coli MurJ) SaMurJ (Staphylococcus aureus MurJ) BsMurJ (Bacillus subtilis MurJ) OFS (outward-facing state) IFS (inward-facing state) RMSD (root mean square deviation) cryo-EM (cryogenic electron microscopy) CTF (contrast...

Abstract Peptidoglycan biogenesis requires membrane flippases to translocate lipid-linked precursors across the cytoplasmic membrane for processing (1). This essential step is mediated by MurJ, the lipid II flippase conserved across all peptidoglycan-producing bacteria (2). While MurJ from diderm bacteria has been structurally resolved in multiple conformational states (3–6), its monoderm homolog remains uncharacterized.

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.