ABSTRACT
Gram-positive bacteria resistant to vancomycin are rare; but they include members of the genera Leuconostoc, Lactobacillus, and Pediococcus, as well as recently emerging vancomycin-resistant strains of Enterococcus faecium and Enterococcus faecalis. Vancomycin, teicoplanin, and several vancomycin derivatives were tested for their activities against vancomycin-resistant gram-positive bacteria. Vancomycin-resistant E. faecium and E. faecalis were generally cross-resistant to other glycopeptides, but some N-substituted vancomycin derivatives were active against the resistant strains, with MICs of 2 to 32 micrograms/ml. These vancomycin derivatives also had significant levels of activity against intrinsically vancomycin-resistant organisms such as Leuconostoc sp. While vancomycin resistance in E. faecium and E. faecalis was inducible, resistance in members of the genera Leuconostoc, Lactobacillus, and Pediococcus appeared to be expressed constitutively. Antibody to a vancomycin-induced membrane protein found in membranes of resistant enterococci did not detect a cross-reacting protein in other vancomycin-resistant species.
Subject(s)
Glycopeptides/pharmacology , Gram-Positive Bacteria/drug effects , Vancomycin/pharmacology , Drug Resistance, Microbial , Gram-Positive Bacteria/growth & development , Leuconostoc/drug effects , Membrane Proteins/metabolism , Pediococcus/drug effects , Time FactorsABSTRACT
Over eighty N-alkyl vancomycins were synthesized by reductive alkylation of vancomycin with the appropriate aldehydes. The N-alkyl vancomycins exhibit greater antibacterial activity than the corresponding N-acyl vancomycins and the parent antibiotic. Some of these semisynthetic vancomycins are five times more active than vancomycin. The N-alkyl vancomycins also show longer elimination half-lives in rats than vancomycin.
Subject(s)
Vancomycin/analogs & derivatives , Animals , Rats , Structure-Activity Relationship , Vancomycin/chemical synthesis , Vancomycin/pharmacologyABSTRACT
Several glycopeptides containing N-acyl groups have been isolated recently. We undertook the synthesis of N-acyl vancomycins, using the active ester method. The in vitro and in vivo antibacterial activity were evaluated, and structure-activity relationship of this series of semisynthetic vancomycins is discussed.
