Synthesis and mode of action of hydrophobic derivatives of the glycopeptide antibiotic eremomycin and des-(N-methyl-D-leucyl)eremomycin against glycopeptide-sensitive and -resistant bacteria

Svetlana S. Printsevskaya, Andrey Y. Pavlov, Evgenia N. Olsufyeva, Elena P. Mirchink, Elena B. Isakova, Marina I. Reznikova, Robert C. Goldman, Arthur A. Branstrom, Eugene R. Baizman, Clifford B. Longley, F. Sztaricskai, G. Batta, Maria N. Preobrazhenskaya

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish
Pages (from-to)1340-1347
Number of pages8
JournalJournal of Medicinal Chemistry
Volume45
Issue number6
DOIs
Publication statusPublished - Mar 14 2002

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Glycopeptides
Bacteria
Anti-Bacterial Agents
Derivatives
Peptidoglycan
Dipeptides
Enterococcus
Cell Wall
Depsipeptides
Cells
eremomycin
Vancomycin
Staphylococcus
Biosynthesis
Lactic Acid
Bioactivity
Leucine
Peptides
Nuclear magnetic resonance
Degradation

ASJC Scopus subject areas

  • Organic Chemistry

Cite this

Synthesis and mode of action of hydrophobic derivatives of the glycopeptide antibiotic eremomycin and des-(N-methyl-D-leucyl)eremomycin against glycopeptide-sensitive and -resistant bacteria. / Printsevskaya, Svetlana S.; Pavlov, Andrey Y.; Olsufyeva, Evgenia N.; Mirchink, Elena P.; Isakova, Elena B.; Reznikova, Marina I.; Goldman, Robert C.; Branstrom, Arthur A.; Baizman, Eugene R.; Longley, Clifford B.; Sztaricskai, F.; Batta, G.; Preobrazhenskaya, Maria N.

In: Journal of Medicinal Chemistry, Vol. 45, No. 6, 14.03.2002, p. 1340-1347.

Research output: Contribution to journalArticle

Printsevskaya, SS, Pavlov, AY, Olsufyeva, EN, Mirchink, EP, Isakova, EB, Reznikova, MI, Goldman, RC, Branstrom, AA, Baizman, ER, Longley, CB, Sztaricskai, F, Batta, G & Preobrazhenskaya, MN 2002, 'Synthesis and mode of action of hydrophobic derivatives of the glycopeptide antibiotic eremomycin and des-(N-methyl-D-leucyl)eremomycin against glycopeptide-sensitive and -resistant bacteria', Journal of Medicinal Chemistry, vol. 45, no. 6, pp. 1340-1347. https://doi.org/10.1021/jm010460i
Printsevskaya, Svetlana S. ; Pavlov, Andrey Y. ; Olsufyeva, Evgenia N. ; Mirchink, Elena P. ; Isakova, Elena B. ; Reznikova, Marina I. ; Goldman, Robert C. ; Branstrom, Arthur A. ; Baizman, Eugene R. ; Longley, Clifford B. ; Sztaricskai, F. ; Batta, G. ; Preobrazhenskaya, Maria N. / Synthesis and mode of action of hydrophobic derivatives of the glycopeptide antibiotic eremomycin and des-(N-methyl-D-leucyl)eremomycin against glycopeptide-sensitive and -resistant bacteria. In: Journal of Medicinal Chemistry. 2002 ; Vol. 45, No. 6. pp. 1340-1347.
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AU - Pavlov, Andrey Y.

AU - Olsufyeva, Evgenia N.

AU - Mirchink, Elena P.

AU - Isakova, Elena B.

AU - Reznikova, Marina I.

AU - Goldman, Robert C.

AU - Branstrom, Arthur A.

AU - Baizman, Eugene R.

AU - Longley, Clifford B.

AU - Sztaricskai, F.

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N2 - 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.

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