Differential inhibition of Staphylococcus aureus PBP2 by glycopeptide antibiotics.
The glycopeptide antibiotics prevent maturation of the bacterial cell wall by binding to the terminal d-alanyl-d-alanine moiety of peptidoglycan precursors, thereby inhibiting the enzymes involved in the final stages of peptidoglycan synthesis. However, there are significant differences in the biological activity of particular glycopeptide derivatives that are not related to their affinity for d-Ala-d-Ala. We compare the ability of vancomycin and a set of clinically relevant glycopeptides to inhibit Staphylococcus aureus PBP2 (penicillin binding protein), the major transglycosylase in a clinically relevant pathogen, S. aureus. We report experiments suggesting that activity differences between glycopeptides against this organism reflect a combination of substrate binding and secondary interactions with key enzymes involved in peptidoglycan synthesis.
Leimkuhler
Catherine
C
Department of Chemistry and Chemical Biology, Harvard University, Cambridge, Massachusetts 02138, USA.
Chen
Lan
L
Barrett
Dianah
D
Panzone
Gianbattista
G
Sun
Binyuan
B
Falcone
Brian
B
Oberthür
Markus
M
Donadio
Stefano
S
Walker
Suzanne
S
Kahne
Daniel
D
D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D004151:Dipeptides / Q000737:chemistry / Q000378:metabolism; D007700:Kinetics; D008826:Microbial Sensitivity Tests; D046915:Penicillin-Binding Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D013211:Staphylococcus aureus / Q000187:drug effects / Q000201:enzymology*; D013379:Substrate Specificity; D014538:Uridine Diphosphate N-Acetylmuramic Acid / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism; D014640:Vancomycin / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*
D000900:Anti-Bacterial Agents; D004151:Dipeptides; D046915:Penicillin-Binding Proteins; D014538:Uridine Diphosphate N-Acetylmuramic Acid; C069249:muramyl-NAc-(pentapeptide)pyrophosphoryl-undecaprenol; C002956:alanylalanine; D014640:Vancomycin