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New derivatives of eremomycin containing 15N or F atoms for NMR study

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Abstract

New semisynthetic derivatives of eremomycin containing 15N or F atoms were obtained for studying the antibiotic-target interaction in intact cells of Gram-positive bacteria by REDOR NMR method. Interaction of the terminal carboxyl group of amino acid 7 (AA7) of eremomycin with amines in the presence of PyBOP and TBTU reagents resulted in the corresponding [15N]-amide, p-fluorobenzylamide, p-fluorophenylpiperazide, and 6-N-(p-fluorobenzyl)aminohexylamide. A selective method of [15N]-amidation of carboxyl group of amino acid 3 (AA3) of carboxyeremomycin was developed, and the amide of eremomycin containing [15N] in AA3 amide group near the antibiotic binding pocket was obtained. Carboxyeremomycin bisamides substituted at AA3 and AA7 and containing two atoms of [15N] or F were obtained from carboxyeremomycin and [15N]NH4Cl or the corresponding p-fluorobenzylamine hydrochloride in the presence of PyBOP at pH ∼8. The Edman degradation of eremomycin p-fluorobenzylamide gave de-(D-MeLeu)-eremomycin p-fluorobenzylamide, a hexapeptide derivative incapable of the antibiotic binding with-D-Ala-D-Ala fragment of growing cell wall peptidoglycan. Among the compounds studied, carboxyeremomycin bis-p-fluorobenzylamide showed the best activity against both the glycopeptides-sensitive and glycopeptides-resistant strains of staphylococci and enterococci.

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Abbreviations

AA:

amino acid residues

Bzl:

benzyl

CM:

carboxymethylcellulose

ESI:

electrospray ionization

GISA:

staphylococci (Staphylococcus aureus) with medium resistance to glycopeptides

GRE:

glycopeptide-resistant enterococci

GRS:

glycopeptide-resistant staphylococci

GSE:

glycopeptide sensitive enterococci

iGln:

isoglutamine

MIC:

minimal inhibitory concentration of antibiotic (μg/ml)

MS:

mass spectometry

PyBOP:

(benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate

REDOR:

Rotation Echo Double Resonance, an NMR method similar to Overhauser decoupling (in solid state)

TBTU:

(benzotriazol-1-yl)-1,1,3,3-bis(tetramethylene) uronium tetrafluoroborate

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Authors and Affiliations

  1. Gause Institute of New Antibiotics, Russian Academy of Medical Sciences, B. Pirogovskaya ul. 11, Moscow, 119021, Russia

    S. E. Solov’eva, S. S. Printsevskaya, E. N. Olsuf’eva & M. N. Preobrazhenskaya

  2. Department of Biochemistry, University of Debrecen, Egyetem tér 1, Debrecen, H-4010, Hungary

    G. Batta

Authors
  1. S. E. Solov’eva
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  2. S. S. Printsevskaya
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  3. E. N. Olsuf’eva
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  4. G. Batta
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  5. M. N. Preobrazhenskaya
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Correspondence to E. N. Olsuf’eva.

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Original Russian Text © S.E. Solov’eva, S.S. Printsevskaya, E.N. Olsuf’eva, G. Batta, M.N. Preobrazhenskaya, 2008, published in Bioorganicheskaya Khimiya, 2008, Vol. 34, No. 6, pp. 831–839.

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Solov’eva, S.E., Printsevskaya, S.S., Olsuf’eva, E.N. et al. New derivatives of eremomycin containing 15N or F atoms for NMR study. Russ J Bioorg Chem 34, 747–754 (2008). https://doi.org/10.1134/S1068162008060162

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  • DOI: https://doi.org/10.1134/S1068162008060162

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