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.
ASJC Scopus subject areas
- Organic Chemistry