Combinatorial Library Approach for the Identification of Synthetic Receptors Targeting Vancomycin-Resistant Bacteria

Practical synthesis of a tetrasaccharide derivative corresponding to ristomycin A and ristocetin A

“…Allyl a-D-glucopyranoside (1) was treated with 1.25 equiv of chlorotriphenylmethane (Tr) and a catalytic amount of 4-dimethylaminopyridine (DMAP) in pyridine at 80°C. Without working up, the mixture was regioselectively silylated with 1.1 equiv of tert-butylchlorodimethylsilane (TBDMSCl) and 2 equiv of imidazole, then benzoylated with benzoyl chloride to give allyl 3, (2) in a total yield of 79%. The 1 H NMR spectrum of 2 gave H-2 (4.0 ppm) and H-6 (3.21, 3.25 ppm) as upfield doublets of doublets, while H-3 (5.80 ppm) and H-4 (5.32 ppm) appeared as downfield triplets, which clearly indicates the correct structure of 2 (see Scheme 1).…”

“…The TMSOTf (0.15 equiv) promoted coupling reaction of 2-O-acetyl-3,4,6-tri-O-benzoyla-D-mannopyranosyl trichloroacetimidate (10) with 8 at 0°C afforded trisacchride 11 in high yield (83%). The structure of 11 was fully assigned from its 2 Cl 2 ) at room temperature for 20 h to get exclusively the corresponding trisaccharide acceptor 12. The chemical shift of H-2 on the mannose residue was moved upfield from 5.45 (in 11) to 4.41 ppm (in 12), strongly supporting the fact that no acyl migration occurred under these reaction conditions.…”

“…1 It has been well established that the biological action of vancomycin-type antibiotics involves reversible binding to nascent bacterial cell-wall peptides terminating in L-Lys-D-Ala-D-Ala through hydrogen bonding. 1,2 This action is also slightly adjusted by the formation of homodimers between two antibiotic monomers. 1 Structural elucidation of ristomycin A and ristocetin A via acetolysis yielded a fully acetylated tetrasaccharide that was determined to have the following sugar sequence: a-D-arabinopyranosyl -(12) -a -D -mannopyranosyl-(12) -[a -L -rhamnopyranosyl - (16)] -b -Dglucopyranose.…”

Importance of the Structure of Vancomycin Binding Pocket in Designing Compounds Active Against Vancomycin-resistant Enterococci (VRE)

“…Fig. 1) to avoid the unfavorable electrostatic interaction with the modified peptidoglycan terminal D-Ala-D-Lac [20,21]; b) the Nterminal was elongated in order to introduce an additional hydrogen-bonding with D-Ala-D-Lac [22]. In order to explore the possible conformational effect, hence the relative three-dimensional orientation of NHs, compound 2 and 3 having D-Leucine (found in vancomycin), and D-leucine, respectively, were synthesized; the glycine was attached to leucine terminal in order to incorporate depicted in the Fig.…”

Clivage sélectif de la liaison D-Ala-D-Lac : nouvelle stratégie pour combattre la résistance à la vancomycine

“…De nombreux efforts ont été entrepris pour trouver de nouveaux antimicrobiens qui pourraient contrer ce mécanisme de résistance à la vancomycine [9][10][11], soit par modification de la vancomycine pour augmenter son affinité pour la terminaison D-Ala-D-Lac, soit via l'inhibition de la voie de synthèse de D-Ala-D-Lac (Figure 1). Ces stratégies ont un désavantage majeur.…”