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 6(B)-methyl ester (MA) and 6(B)-decarboxy-6(B)-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 similar to 64 mu g/ml) against strains of Enterococcus for which vancomycin and teicoplanin MICs were greater than or equal to 128 mu g/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.