Mechanism of action of the mannopeptimycins, a novel class of glycopeptide antibiotics active against vancomycin-resistant gram-positive bacteria.
The naturally occurring mannopeptimycins (formerly AC98-1 through AC98-5) are a novel class of glycopeptide antibiotics that are active against a wide variety of gram-positive bacteria. The structures of the mannopeptimycins suggested that they might act by targeting cell wall biosynthesis, similar to other known glycopeptide antibiotics; but the fact that the mannopeptimycins retain activity against vancomycin-resistant organisms suggested that they might have a unique mode of action. By using a radioactive mannopeptimycin derivative bearing a photoactivation ligand, it was shown that mannopeptimycins interact with the membrane-bound cell wall precursor lipid II [C(55)-MurNAc-(peptide)-GlcNAc] and that this interaction is different from the binding of other lipid II-binding antibiotics such as vancomycin and mersacidin. The antimicrobial activities of several mannopeptimycin derivatives correlated with their affinities toward lipid II, suggesting that the inhibition of cell wall biosynthesis was primarily through lipid II binding. In addition, it was shown that mannopeptimycins bind to lipoteichoic acid in a rather nonspecific interaction, which might facilitate the accumulation of antibiotic on the bacterial cell surface.
Ruzin
Alexey
A
Wyeth Research, Pearl River, New York 10965, USA. ruzina@wyeth.com
Singh
Guy
G
Severin
Anatoly
A
Yang
Youjun
Y
Dushin
Russell G
RG
Sutherland
Alan G
AG
Minnick
Albert
A
Greenstein
Michael
M
May
Michael K
MK
Shlaes
David M
DM
Bradford
Patricia A
PA
D000345:Affinity Labels; D000900:Anti-Bacterial Agents / Q000378:metabolism / Q000494:pharmacology*; D001425:Bacterial Outer Membrane Proteins; D001426:Bacterial Proteins / Q000378:metabolism; D001667:Binding, Competitive / Q000187:drug effects; D002352:Carrier Proteins / Q000378:metabolism; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D002855:Chromatography, Thin Layer; D003470:Culture Media; D004926:Escherichia coli / Q000187:drug effects; D029968:Escherichia coli Proteins; D006020:Glycopeptides; D006094:Gram-Positive Bacteria / Q000187:drug effects* / Q000378:metabolism; D006602:Hexosyltransferases / Q000378:metabolism; D002267:Muramoylpentapeptide Carboxypeptidase / Q000378:metabolism; D046915:Penicillin-Binding Proteins; D010457:Peptidoglycan / Q000096:biosynthesis; D010458:Peptidyl Transferases / Q000378:metabolism; D011485:Protein Binding; D011991:Receptors, Virus; D013211:Staphylococcus aureus / Q000187:drug effects; D013212:Staphylococcus epidermidis / Q000187:drug effects; D020713:Vancomycin Resistance
D000345:Affinity Labels; D000900:Anti-Bacterial Agents; D001425:Bacterial Outer Membrane Proteins; D001426:Bacterial Proteins; D002352:Carrier Proteins; D003470:Culture Media; D029968:Escherichia coli Proteins; C050900:FhuA protein, E coli; D006020:Glycopeptides; D046915:Penicillin-Binding Proteins; D010457:Peptidoglycan; D011991:Receptors, Virus; C478082:mannopeptimycin; D010458:Peptidyl Transferases; D006602:Hexosyltransferases; D002267:Muramoylpentapeptide Carboxypeptidase