19F NMR in the measurement of binding affinities of chloroeremomycin to model bacterial cell-wall surfaces that mimic VanA and VanB resistance.
BACKGROUND
The emergence of bacteria that are resistant to vancomycin, the drug of choice against methicillin-resistant Staphylococcus aureus, has made the study of the binding characteristics of glycopeptides to biologically relevant depsipeptides important. These depsipeptides, terminating in D-alanyl-D-lactate, mimic the cell-wall precursors of resistant bacteria.


RESULTS
The use of 19F-labelled ligands in the study of the therapeutically important vancomycin series of antibiotics is demonstrated. The substantial simplification of spectra that occurs when such labelled ligands are employed is used in the measurement of binding affinities of depsipeptides to chloroeremomycin (CE). Large enhancements of binding affinities are found at a model bacterial cell-wall surface (constituted from depsipeptides that are anchored into vesicles) relative to those measured in free solution.


CONCLUSIONS
Surface-enhanced binding, previously shown for strongly dimerizing glycopeptide antibiotics to normal -D-alanyl-D-alanine-terminating cell-wall precursors, is now demonstrated for CE to the surface of models of VanA- and VanB-resistant bacteria. The effect of depsipeptide chain length is shown to be critically important in producing and maximizing this enhancement.
Entress
R M
RM
Cambridge Centre for Molecular Recognition, University Chemical Laboratory, UK.
Dancer
R J
RJ
O'Brien
D P
DP
Try
A C
AC
Cooper
M A
MA
Williams
D H
DH
D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000378:metabolism*; D019729:Carbon-Oxygen Ligases / Q000378:metabolism*; D002473:Cell Wall / Q000737:chemistry / Q000378:metabolism*; D004352:Drug Resistance, Microbial; D016983:Enterococcus / Q000187:drug effects / Q000378:metabolism; D005461:Fluorine; D009682:Magnetic Resonance Spectroscopy / Q000379:methods; D008954:Models, Biological; D011485:Protein Binding / Q000187:drug effects; D013499:Surface Properties; D014640:Vancomycin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology
D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; C071437:VanA ligase, Bacteria; C079913:VanB protein, Enterococcus; C112142:chloroeremomycin; D005461:Fluorine; D014640:Vancomycin; D019729:Carbon-Oxygen Ligases