RESUMO
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) Assuntos
Antibacterianos/química
, Teicoplanina/análogos & derivados
, Antibacterianos/síntese química
, Antibacterianos/farmacologia
, Farmacorresistência Bacteriana
, Glicopeptídeos
, Bactérias Gram-Positivas/efeitos dos fármacos
, Interações Hidrofóbicas e Hidrofílicas
, Espectroscopia de Ressonância Magnética
, Testes de Sensibilidade Microbiana
, Espectrometria de Massas por Ionização por Electrospray
, Relação Estrutura-Atividade
, Teicoplanina/síntese química
, Teicoplanina/química
, Teicoplanina/farmacologia
, Vancomicina/análogos & derivados
, Vancomicina/síntese química
, Vancomicina/química
, Vancomicina/farmacologia
RESUMO
A variety of semisynthetic derivatives of natural antibacterial glycopeptide antibiotics such as vancomycin, eremomycin, ristocetin A, teicoplanin A(2)-2, DA-40926, their aglycons, and also the products of their partial degradation with a destroyed or modified peptide core show marked anti-retroviral activity in cell culture. In particular, aglycon antibiotic derivatives containing various substituents of a preferably hydrophobic nature displayed activity against human immunodeficiency virus type 1 (HIV-1), HIV-2, and Moloney murine sarcoma virus at a 50% inhibitory concentration in the lower micromolar (1-5 microM) concentration range while not being cytostatic against human lymphocytic cells at 250 microM or higher. The mode of anti-HIV action of the antibiotic aglycon derivatives could be ascribed to inhibition of the viral entry process.
Assuntos
Antibacterianos/química , Antivirais/síntese química , Glicopeptídeos , HIV-1/efeitos dos fármacos , HIV-2/efeitos dos fármacos , Vírus do Sarcoma Murino de Moloney/efeitos dos fármacos , Animais , Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/química , Fármacos Anti-HIV/farmacologia , Antivirais/química , Antivirais/farmacologia , Linhagem Celular , Efeito Citopatogênico Viral/efeitos dos fármacos , Fibroblastos/efeitos dos fármacos , Fibroblastos/virologia , Humanos , Camundongos , Relação Estrutura-AtividadeRESUMO
Des-(N-methyl-D-leucyl)eremomycin was obtained by Edman degradation of eremomycin. Derivatives with a hydrophobic substituent at the exterior of the molecule were then synthesized, and their antibacterial activities were compared with similar derivatives of eremomycin. Comparison of derivatives of eremomycin containing the n-decyl or p-(p-chlorophenyl)benzyl substituent in the eremosamine moiety (N') and n-decyl or p-(p-chlorophenyl)benzylamides with similar derivatives of eremomycin possessing the damaged peptide core (a defective binding pocket) showed that compounds of both types are almost equally active against glycopeptide-resistant strains of enterococci (GRE), whereas eremomycin derivatives are more active against staphylococci. Hydrophobic 7d-alkylaminomethylated derivatives of eremomycin (9, 10) demonstrated similar antibacterial properties. Since the basic mode of action of glycopeptide antibiotics involves binding to cell wall intermediates terminating in -D-Ala-D-Ala and this interaction is seriously decreased in the hexapeptide derivatives (lacking the critical N-methyl-D-leucine), we suggest that these hydrophobic derivatives may inhibit peptidoglycan synthesis in the absence of dipeptide binding. NMR binding experiments using Ac-D-Ala-D-Ala show that binding constants of these hexapeptide derivativies are decreased in comparison with the corresponding heptapeptides with intact binding pocket. This is in agreement with the decreased biological activity of the hexapeptide derivatives against vancomycin-sensitive strains in comparison with the activity of parent compounds. Binding to the lactate cell wall analogue Ac-D-Ala-D-Lac with decylamide of eremomycin 8 was not observed, demonstrating that the interaction with this target in GRE does not occur. While hydrophobic glycopeptide derivatives retain the ability to inhibit the synthesis of peptidoglycan in manner of natural glycopeptides, biochemical investigation supports the hypothesis that they inhibit the transglycosylase stage of bacterial peptidoglycan biosynthesis even in the absence of dipeptide or depsipeptide binding.