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 approximately 64 micrograms/ml) against strains of Enterococcus for which vancomycin and teicoplanin MICs were > or = 128 micrograms/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.
Malabarba
A
A
Marion Merrell Dow Research Institute, Lepetit Research Center, Gerenzano (Varese), Italy.
Ciabatti
R
R
Scotti
R
R
Goldstein
B P
BP
Ferrari
P
P
Kurz
M
M
Andreini
B P
BP
Denaro
M
M
D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002851:Chromatography, High Pressure Liquid; D004352:Drug Resistance, Microbial; D016983:Enterococcus / Q000187:drug effects*; D009682:Magnetic Resonance Spectroscopy; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D013329:Structure-Activity Relationship; D017334:Teicoplanin / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D014640:Vancomycin / Q000494:pharmacology
C054981:A 40926; D000900:Anti-Bacterial Agents; C096603:MDL 63042; D017334:Teicoplanin; D014640:Vancomycin; C096602:MDL 63246