Katanosin B and plusbacin A3, inhibitors of peptidoglycan synthesis in methicillin-resistant Staphylococcus aureus

Both katanosin B and plusbacin A, 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 mug/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 E and plusbacin A, inhibited the formation of lipid intermediates, with 50% inhibitory concentrations (IC(50)s) of 2.2 and 2.3 mug/ml, respectively, and inhibited the formation of nascent peptidoglycan,,vith IC(50)s of 0.8 and 0.4 mug/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 IC50 of 4.1 mug/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.