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J. Biol. Chem., Vol. 276, Issue 3, 1772-1779, January 19, 2001
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From the Unlike numerous pore-forming amphiphilic peptide
antibiotics, the lantibiotic nisin is active in nanomolar
concentrations, which results from its ability to use the lipid-bound
cell wall precursor lipid II as a docking molecule for subsequent pore
formation. Here we use genetically engineered nisin variants to
identify the structural requirements for the interaction of the peptide with lipid II. Mutations affecting the conformation of the N-terminal part of nisin comprising rings A through C, e.g.
[S3T]nisin, led to reduced binding and increased the peptide
concentration necessary for pore formation. The binding constant for
the S3T mutant was 0.043 × 107
M
Specific Binding of Nisin to the Peptidoglycan Precursor Lipid II
Combines Pore Formation and Inhibition of Cell Wall Biosynthesis
for Potent Antibiotic Activity*
,
,,**
Institut für Medizinische
Mikrobiologie und Immunologie der Universität Bonn, D-53105 Bonn,
Germany, the § Department of Biochemistry of Membranes,
Center for Biomembranes and Lipid Enzymology, Institute of
Biomembranes, Utrecht University, Padualaan 8, 3584 CH, Utrecht, The
Netherlands, and the ¶ NIZO Food Research, Microbial
Ingredients Section, P.O. Box 20, 6710 BA, Ede, The Netherlands
1 compared with 2 × 107
M1 for the wild-type peptide, and the minimum
concentration for pore formation increased from the 1 nM to
the 50 nM range. In contrast, peptides mutated in the
flexible hinge region, e.g. [
N20/M21]nisin, were
completely inactive in the pore formation assay, but were reduced to
some extent in their in vivo activity. We found the
remaining in vivo activity to result from the unaltered capacity of the mutated peptide to bind to lipid II and thus to inhibit
its incorporation into the peptidoglycan network. Therefore, through
interaction with the membrane-bound cell wall precursor lipid II, nisin
inhibits peptidoglycan synthesis and forms highly specific pores. The
combination of two killing mechanisms in one molecule potentiates
antibiotic activity and results in nanomolar MIC values, a strategy
that may well be worth considering for the construction of novel antibiotics.
*
This work was supported by a short term fellowship from the
European Molecular Biology Organization (EMBO) (to I. W.), by The
Netherlands Foundation for Chemical Research (SON) with financial aid
from The Netherlands Foundation of Scientific Research (NWO), the
Foundation of Applied Science (STW) (to E. B., and C. V. K.) by the
Bundesministerium für Forschung und Technologie (BMBF), and by
the BONFOR Programme of the Medical Faculty of the University of Bonn.The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
Present Address: Dept. of Genetics, Inst. of Biomolecular
Sciences and Biotechnology, University of Groningen, P.O. Box 14, 9750 AA Harem, The Netherlands.
**
To whom correspondence should be addressed: Institut für
Medizinische Mikrobiologie und Immunologie der Universität
Bonn, Sigmund-Freud-Str. 25, 53105 Bonn, Germany. Tel:. 49 (228) 287 5704; Fax: 49 (228) 287 4808; E-mail:
sahl@mibi03.meb.uni-bonn.de.
Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.
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