136577-07-6Relevant articles and documents
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
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
, p. 14911 - 14915 (2018)
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.
Crystal structures of two vancomycin complexes with phosphate and N-AcetylD-Ala. structural comparison between low-affinity and high-affinity ligand complexes of vancomycin
Kikuchi, Takanori,Karki, Shyam,Fujisawa, Ikuhide,Matsushima, Yoshitaka,Nitanai, Yasushi,Aoki, Katsuyuki
experimental part, p. 391 - 400 (2010/07/08)
Crystal structures of two vancomycin complexes with phosphate and N-acetylD-Ala (AcDA) were determined. Each complex involves two crystallographically independent vancomycin molecules (V1 and V2) in the asymmetric unit, which form a usually observed back-to-back arranged vancomycin dimer V1V2 with two disaccharide chains packed in a head-to-head manner, but only one of the two ligand-binding sites is occupied. Comparison of the published crystal structures of low-affinity (small in molecular size) ligand complexes of vancomycin with high-affinity (large) ligand complexes reveals that when the high-affinity ligand binds, three structural factors (hydrogen-bonding interactions between the two peptide-backbones and hydrophobic intra-dimer sugarring and ring (face)ring (edge) interactions) work to enhance the stabilization of the back-to-back dimer-interface, an important factor that is believed to promote antibacterial activity. It has also been revealed, by examining the high-affinity ligand complexes (including N-acetylDAlaD-Ala), that sugarligand interaction could cause different affinities of the two halves of the dimer; this is a factor responsible for the failure of the ligand binding to V1 in the AcDA complex. Possible scenarios for the formation of vancomycin complexes with low-affinity as well as high-affinity ligands are presented.
