Role of the Glycopeptide Framework in the Antibacterial Activity of Hydrophobic Derivatives of Glycopeptide Antibiotics

• Published in: Journal of medicinal chemistry 2003-03, Vol.46 (7), p.1204-1209
• Main Authors: Printsevskaya, Svetlana S, Pavlov, Andrey Y, Olsufyeva, Evgenia N, Mirchink, Elena P, Preobrazhenskaya, Maria N
• Format: Article
• Language: English
• Subjects: Anti-Bacterial Agents - chemical synthesis; Anti-Bacterial Agents - chemistry; Anti-Bacterial Agents - pharmacology; Drug Resistance, Bacterial; Enterococcus; glycopeptide antibiotics; Glycopeptides; Gram-Positive Bacteria - drug effects; Hydrophobic and Hydrophilic Interactions; Magnetic Resonance Spectroscopy; Microbial Sensitivity Tests; peptidoglycans; Spectrometry, Mass, Electrospray Ionization; Structure-Activity Relationship; Teicoplanin - analogs & derivatives; Teicoplanin - chemical synthesis; Teicoplanin - chemistry; Teicoplanin - pharmacology; Vancomycin - analogs & derivatives; Vancomycin - chemical synthesis; Vancomycin - chemistry; Vancomycin - pharmacology
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm020320o

The antibacterial properties of glycopeptide antibiotics are based on their interaction with the d-Ala-d-Ala containing pentapeptide of bacterial peptidoglycan. The hydrophobic amides of vancomycin (1), teicoplanin (2), teicoplanin aglycon (3), and eremomycin (4) were compared with similar amides of minimally or low active des-(N-methyl-d-leucyl)eremomycin (5), eremomycin aglycon (6), des-(N-methyl-d-leucyl)eremomycin aglycon (7), and a teicoplanin degradation product TB-TPA (8). All hydrophobic amides of 1, 3, 4, and 6 were almost equally active against glycopeptide-resistant enterococci (GRE) [minimum inhibitory concentrations (MIC) ≤ 4 μg/mL] and had better activity against Gram-positive strains sensitive to glycopeptides than against GRE. Extensive degradation of the glycopeptide framework in amides of 7 and 8 led to a decrease of anti-GRE activity (MIC = 16−64 μg/mL), and for these derivatives MIC values for bacterial strains sensitive and resistant to glycopeptides were very close. These results suggest that in sensitive bacteria two mechanisms of action are operating for the hydrophobic derivatives of glycopeptide antibiotics with the nondamaged peptide coreinteraction with the d-Ala-d-Ala moiety and the inhibition of bacterial membrane bound enzymatic reactions, whereas for GRE lacking the d-Ala-d-Ala fragment, only the second mechanism is operating. It appears that a minimal glycopeptide core is required for activity, and that more extensive degradation results in a serious decrease of antibacterial activity.