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Antimicrobial Agents and Chemotherapy, January 1998, p. 154-160, Vol. 42, No. 1
0066-4804/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.

The Lantibiotic Mersacidin Inhibits Peptidoglycan Synthesis by Targeting Lipid II

Heike Brötz,1 Gabriele Bierbaum,1 Klaus Leopold,2 Peter E. Reynolds,3 and Hans-Georg Sahl1,*

Institut für Medizinische Mikrobiologie und Immunologie, Universität Bonn, D-53105 Bonn,1 and Institut für Biochemie der Medizinischen Fakultät, Universität Erlangen, D-91054 Erlangen,2 Germany, and Department of Biochemistry, University of Cambridge, Cambridge CB2 1QW, United Kingdom3

Received 28 April 1997/Returned for modification 27 August 1997/Accepted 3 November 1997

The lantibiotic mersacidin exerts its bactericidal action by inhibition of peptidoglycan biosynthesis. It interferes with the membrane-associated transglycosylation reaction; during this step the ultimate monomeric peptidoglycan precursor, undecaprenyl-pyrophosphoryl-MurNAc-(pentapeptide)-GlcNAc (lipid II) is converted into polymeric nascent peptidoglycan. In the present study we demonstrate that the molecular basis of this inhibition is the interaction of mersacidin with lipid II. The adsorption of [14C]mersacidin to growing cells, as well as to isolated membranes capable of in vitro peptidoglycan synthesis, was strictly dependent on the availability of lipid II, and antibiotic inhibitors of lipid II formation strongly interfered with this binding. Direct evidence for the interaction was provided by studies with isolated lipid II. [14C]mersacidin associated tightly with [14C]lipid II micelles; the complex was stable even in the presence of 1% sodium dodecyl sulfate. Furthermore, the addition of isolated lipid II to the culture broth efficiently antagonized the bactericidal activity of mersacidin. In contrast to the glycopeptide antibiotics, complex formation does not involve the C-terminal D-alanyl-D-alanine moiety of the lipid intermediate. Thus, the interaction of mersacidin with lipid II apparently occurs via a binding site which is not targeted by any antibiotic currently in use.

* Corresponding author. Mailing address: Institut für Medizinische Mikrobiologie und Immunologie der Universität Bonn, Sigmund-Freud-Str. 25, D-53105 Bonn, Germany. Phone: (49)228/2875704. Fax: (49)228/2874808. E-mail: Sahl{at}mibi03.meb.uni-Bonn.de.

Antimicrobial Agents and Chemotherapy, January 1998, p. 154-160, Vol. 42, No. 1
0066-4804/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.


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