[New derivatives of eremomycin containing (15)n or f atoms for NMR study].
New semisynthetic derivatives of eremomycin containing (15)N or F atom 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 [(15)N]-amide, p-fluorobenzylamide, p-fluorophenylpiperazide, and 6-N-(p-fluorobenzyl)aminohexylamide. A selective method of [(15)N]-amidation of carboxyl group of amino acid 3 (AA3) of carboxyeremomycin was developed, and the amide of eremomycin containing [(15)N] in AA3 amide group near the antibiotic binding pocket was obtained. Carboxyeremomycin bisamides substituted at AA3 and AA7 and containing two atoms of [(15)N] or F were obtained from carboxyeremomycin and [(15)N]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.
Solov'eva
S E
SE
Gause Institute of New Antibiotics, Russian Academy of Medical Sciences, B. Pirogovskaya ul. 11, Moscow, 119021, Russia.
Printsevskaia
S S
SS
Olsuf'eva
E N
EN
Batta
G
G
Preobrazhenskaia
M N
MN
D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D024881:Drug Resistance, Bacterial / Q000187:drug effects; D016983:Enterococcus / Q000254:growth & development*; D005459:Fluorides / Q000737:chemistry; D006020:Glycopeptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D009587:Nitrogen Isotopes / Q000737:chemistry; D013210:Staphylococcus / Q000254:growth & development*
D000900:Anti-Bacterial Agents; D006020:Glycopeptides; D009587:Nitrogen Isotopes; C053759:eremomycin; D005459:Fluorides