New Semisynthetic Glycopeptides MDL 63, 246 and MDL 63, 042, and Other Amide Derivatives of Antibiotic A-40, 926 Active against Highly Glycopeptide-resistant VanA Enterococci

A series of amide derivatives of natural glycopeptide A-40, 926 (A), its 6B-methyl ester (MA) and 6B-decarboxy-6B-hydroxymethyl derivative (RA) were prepared with the aim of obtaining activity against glycopeptide-resistant enterococci. These compounds are structurally related to a class of amides of 34-de(acetylglucosaminyl)-34-deoxy teicoplanin which showed interesting activity against strains of Enterococcus faecalis and E. faecium highly resistant to both vancomycin and teicoplanin. Among them, RA-amides MDL 63, 246 and MDL 63, 042 were the most active derivatives against several Gram-positive bacteria, including VanB and VanC enterococci, and were moderately active (MIC range 0.5-64μg/ml) against strains of Enterococcus for which vancomycin and teicoplanin MICs were ≥128μg/ml. The chemical rationale and the synthesis of these new series of glycopeptide derivatives are described. Preliminary in vitro data are reported and structure-activity relationships are discussed.