Synthesis of lipid-carbohydrate-peptidyl-RNA conjugates to explore the limits imposed by the substrate specificity of cell wall enzymes on the acquisition of drug resistance

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Fonvielle, Matthieu | Bouhss, Ahmed | Hoareau, Coralie | Patin, Delphine | Mengin-Lecreulx, Dominique | Iannazzo, Laura | Sakkas, Nicolas | El Sagheer, Affaf | Brown, Tom | Ethève-Quelquejeu, Mélanie | Arthur, Michel

Edité par CCSD ; Wiley-VCH Verlag -

International audience. 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.

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