Cookies on this website
We use cookies to ensure that we give you the best experience on our website. If you click 'Continue' we'll assume that you are happy to receive all cookies and you won't see this message again. Click 'Find out more' for information on how to change your cookie settings.

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

DOI

10.1002/chem.201802360

Type

Journal article

Journal

Chemistry

Publication Date

09/10/2018

Volume

24

Pages

14911 - 14915

Keywords

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