Vancomycin derivatives that inhibit peptidoglycan biosynthesis without binding D-Ala-D-Ala.
Vancomycin is an important drug for the treatment of Gram-positive bacterial infections. Resistance to vancomycin has begun to appear, posing a serious public health threat. Vancomycin analogs containing modified carbohydrates are very active against resistant microorganisms. Results presented here show that these carbohydrate derivatives operate by a different mechanism than vancomycin; moreover, peptide binding is not required for activity. It is proposed that carbohydrate-modified vancomycin compounds are effective against resistant bacteria because they interact directly with bacterial proteins involved in the transglycosylation step of cell wall biosynthesis. These results suggest new strategies for designing glycopeptide antibiotics that overcome bacterial resistance.
Ge
M
M
Department of Chemistry, Princeton University Princeton, NJ 08544, USA.
Chen
Z
Z
Onishi
H R
HR
Kohler
J
J
Silver
L L
LL
Kerns
R
R
Fukuzawa
S
S
Thompson
C
C
Kahne
D
D
D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D002241:Carbohydrates / Q000737:chemistry; D002462:Cell Membrane / Q000378:metabolism; D004151:Dipeptides / Q000378:metabolism*; D015195:Drug Design; D004352:Drug Resistance, Microbial; D013293:Enterococcus faecalis / Q000187:drug effects; D004926:Escherichia coli / Q000187:drug effects / Q000378:metabolism; D006031:Glycosylation; D006602:Hexosyltransferases / Q000037:antagonists & inhibitors / Q000378:metabolism; D050356:Lipid Metabolism; D008826:Microbial Sensitivity Tests; D010457:Peptidoglycan / Q000096:biosynthesis*; D046928:Peptidoglycan Glycosyltransferase; D011485:Protein Binding; D011498:Protein Precursors / Q000378:metabolism; D013329:Structure-Activity Relationship; D014640:Vancomycin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*
D000900:Anti-Bacterial Agents; D002241:Carbohydrates; D004151:Dipeptides; D010457:Peptidoglycan; D011498:Protein Precursors; C002956:alanylalanine; D014640:Vancomycin; D006602:Hexosyltransferases; D046928:Peptidoglycan Glycosyltransferase