Synthesis of hydrophobic N'-mono and N',N"-double alkylated eremomycins inhibiting the transglycosylation stage of bacterial cell wall biosynthesis.
A series of hydrophobic N'-mono and N',N"-double alkylated derivatives of the glycopeptide antibiotic eremomycin were synthesized by reductive alkylation after preliminary protection of the N-terminal amino group of the peptide backbone. The investigation of the antibacterial activity in vitro showed that N'-C10H21- and N'-p-(p-chlorophenyl)benzyl derivatives of eremomycin are the most active against vancomycin-resistant enterococci among the compounds obtained though they are less effective than the corresponding lipophilic derivatives of vancomycin. The introduction of two hydrophobic substituents led to a decrease in activity against both susceptible and resistant bacteria. The biochemical evaluation of the mode of action revealed that in addition to binding to D-Ala-D-Ala these compounds also have an alternative mechanism of action that does not require substrate binding.
Pavlov
A Y
AY
Institute of New Antibiotics of the Russian Academy of Medical Sciences, Moscow.
Miroshnikova
O V
OV
Printsevskaya
S S
SS
Olsufyeva
E N
EN
Preobrazhenskaya
M N
MN
Goldman
R C
RC
Branstrom
A A
AA
Baizman
E R
ER
Longley
C B
CB
D000478:Alkylation; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D002473:Cell Wall / Q000187:drug effects / Q000378:metabolism; D004352:Drug Resistance, Microbial; D016983:Enterococcus / Q000187:drug effects* / Q000378:metabolism; D006020:Glycopeptides; D006031:Glycosylation / Q000187:drug effects; D008826:Microbial Sensitivity Tests; D013329:Structure-Activity Relationship; D013499:Surface Properties; D014640:Vancomycin / Q000494:pharmacology
D000900:Anti-Bacterial Agents; D006020:Glycopeptides; C053759:eremomycin; D014640:Vancomycin