Semiquantitation of cooperativity in binding of vancomycin-group antibiotics to vancomycin-susceptible and -resistant organisms.
The association of vancomycin group antibiotics with the growing bacterial cell wall was investigated by using the cell wall precursor analog di-N-acetyl-Lys-D-Ala-D-Ala in competition binding experiments. The affinities of the antibiotics for the -D-Ala-D-Ala-containing cell wall precursors of Bacillus subtilis ATCC 6633 (a model for vancomycin-susceptible gram-positive bacteria) and for the -D-Ala-D-Lac-containing cell wall precursors of Leuconostoc mesenteroides (a model for vancomycin-resistant strains of Enterococcus faecium and Enterococcus faecalis) were determined by a whole-cell assay. The binding of strongly dimerizing antibiotics such as eremomycin to the bacterial surface was thus shown to be enhanced by up to 2 orders of magnitude (relative to the binding in free solution) by the chelate effect, whereas weakly dimerizing antibiotics like vancomycin and antibiotics carrying lipid tails (teicoplanin) benefited less (ca. 1 order of magnitude). The affinity measured in this way correlates well with the MIC of the antibiotic, and a consequence of this is that future design of semisynthetic vancomycin-group antibiotics should attempt to incorporate chelate effect-enhancing structural features.
Beauregard
D A
DA
Cambridge Centre for Molecular Recognition, University Chemical Laboratory, England.
Maguire
A J
AJ
Williams
D H
DH
Reynolds
P E
PE
D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D001412:Bacillus subtilis / Q000187:drug effects*; D001667:Binding, Competitive; D002462:Cell Membrane / Q000187:drug effects; D004352:Drug Resistance, Microbial; D006860:Hydrogen Bonding; D007934:Leuconostoc / Q000187:drug effects*; D013329:Structure-Activity Relationship; D014640:Vancomycin / Q000031:analogs & derivatives / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology
D000900:Anti-Bacterial Agents; D014640:Vancomycin