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Conjugation of RNA with multiple partners to obtain mimics of complex biomolecules is limited by the identification of orthogonal reactions. Here, lipid-carbohydrate-peptidyl-RNA conjugates were obtained by post-functionalization reactions, solid-phase synthesis, and enzymatic steps, to generate molecules mimicking the substrates of FmhB, an essential peptidoglycan synthesis enzyme of Staphylococcus aureus. Mimics of Gly-tRNAGly and lipid intermediate II (undecaprenyl-diphospho-disaccharide-pentapeptide) were combined in a single "bi-substrate" inhibitor (IC50 =56 nm). The synthetic route was exploited to generate substrates and inhibitors containing d-lactate residue (d-Lac) instead of d-Ala at the C-terminus of the pentapeptide stem, a modification responsible for vancomycin resistance in the enterococci. The substitution impaired recognition of peptidoglycan precursors by FmhB. The associated fitness cost may account for limited dissemination of vancomycin resistance genes in S. aureus.

Original publication




Journal article



Publication Date





14911 - 14915


Fem, RNA conjugates, Staphylococcus aureus, VanA, vancomycin, Bacterial Proteins, Carbohydrates, Cell Wall, Drug Discovery, Drug Resistance, Bacterial, Enzyme Inhibitors, Humans, Lipids, Peptidoglycan, RNA, Solid-Phase Synthesis Techniques, Staphylococcal Infections, Staphylococcus aureus, Substrate Specificity