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J Bacteriol. 1968 August; 96(2): 374-382
Copyright © 1968 American Society for Microbiology. All Rights Reserved.

Reversal of the Vancomycin Inhibition of Peptidoglycan Synthesis by Cell Walls¹

^a Biochemistry Division, Department of Chemistry, Northwestern University, Evanston, Illinois 60201

ABSTRACT

Addition of cell walls to the peptidoglycan synthetase-acceptor system containing vancomycin (50 µg/ml) prevented the inhibition by the antibiotic. In addition, the inhibition of incorporation of [¹⁴C]muramyl-pentapeptide into peptidoglycan in the presence of vancomycin was reversed by the addition of cell walls to the assay mixture at 60 min. Cell walls previously saturated with vancomycin lost their ability to reverse the inhibition by the antibiotic. The inhibition of peptidoglycan synthesis by ristocetin was partially reversed by the addition of cell walls. The initial stage in peptidoglycan synthesis is catalyzed by phospho-N-acetyl(NAc)muramyl-pentapeptide translocase (uridine 5'-phosphate) according to the reaction: UDP-NAc-muramyl-pentapeptide + acceptor acceptor-phospho-NAc-muramyl-pentapeptide + UMP where acceptor is C₅₅-isoprenoid alcohol phosphate. Vancomycin stimulates the transfer of phospho-NAc-muramyl-pentapeptide to the acceptor, and the addition of cell walls to this assay mixture prevented the stimulation of transfer. In addition to the transfer reaction, the enzyme catalyzes the exchange of [³H]uridine monophosphate (UMP) with UDP-NAc-muramyl-pentapeptide. The exchange reaction is effectively inhibited by vancomycin. For example, 60 µg of vancomycin per ml inhibited the rate of exchange by 50%. Addition of cell walls restored the exchange of UMP with the UMP moiety of UDP-NAc-muramyl-pentapeptide. Thus, cell walls appeared to have a higher affinity for vancomycin than did either the peptidoglycan synthetase-acceptor system or phospho-NAc-muramyl-pentapeptide translocase. These results provide support for the proposal made by Best and Durham that the effective binding of vancomycin to the cell wall could result in the inhibition of transfer of membrane-associated peptidoglycan chains to the growing wall.

² Present address: Bose Institute, Calcutta, India.

³ Supported by U.S. Public Health Service Research Career Development Program Award 1-K3-AI-6950 from the National Institute of Allergy and Infectious Diseases.

¹ Presented in part at the 67th Annual Meeting of the American Society for Microbiology, New York, N.Y., 30 April–4 May 1967.

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