Katanosin B and plusbacin A(3), inhibitors of peptidoglycan synthesis in methicillin-resistant Staphylococcus aureus.
Both katanosin B and plusbacin A(3) are naturally occurring cyclic depsipeptide antibiotics containing a lactone linkage. They showed strong antibacterial activity against methicillin-resistant Staphylococcus aureus and VanA-type vancomycin-resistant enterococci, with MICs ranging from 0.39 to 3.13 microg/ml, as well as against other gram-positive bacteria. They inhibited the incorporation of N-acetylglucosamine, a precursor of cell wall synthesis, into peptidoglycan of S. aureus whole cells at concentrations close to their MICs. In vitro studies with a wall-membrane particulate fraction of S. aureus showed that katanosin B and plusbacin A(3) inhibited the formation of lipid intermediates, with 50% inhibitory concentrations (IC(50)s) of 2.2 and 2.3 microg/ml, respectively, and inhibited the formation of nascent peptidoglycan, with IC(50)s of 0.8 and 0.4 microg/ml, respectively. Vancomycin, a well-known inhibitor of transglycosylation, did not inhibit the formation of lipid intermediates but did inhibit the formation of nascent peptidoglycan, with an IC(50) of 4.1 microg/ml. Acetyl-Lys-D-Ala-D-Ala, an analog of the terminus of the lipid intermediates, effectively suppressed the inhibition of transglycosylation by vancomycin, but did not suppress those by katanosin B and plusbacin A(3). These results indicate that the antibacterial activity of katanosin B and plusbacin A(3) is due to blocking of transglycosylation and its foregoing steps of cell wall peptidoglycan synthesis via a mechanism differing from that of vancomycin.
Maki
H
H
Discovery Research Laboratories, Shionogi & Co., Ltd., Osaka, Japan. hideki.maki@shionogi.co.jp
Miura
K
K
Yamano
Y
Y
D000117:Acetylglucosamine / Q000378:metabolism / Q000494:pharmacology; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D002473:Cell Wall / Q000187:drug effects / Q000378:metabolism; D002478:Cells, Cultured; D047630:Depsipeptides; D016983:Enterococcus / Q000187:drug effects*; D016106:Methicillin Resistance; D008826:Microbial Sensitivity Tests; D010455:Peptides; D010456:Peptides, Cyclic / Q000494:pharmacology*; D010457:Peptidoglycan / Q000096:biosynthesis*; D013211:Staphylococcus aureus / Q000187:drug effects* / Q000378:metabolism; D014640:Vancomycin / Q000494:pharmacology
D000900:Anti-Bacterial Agents; D047630:Depsipeptides; D010455:Peptides; D010456:Peptides, Cyclic; D010457:Peptidoglycan; C433785:plusbacin A3; C056790:katanosin B; D014640:Vancomycin; D000117:Acetylglucosamine