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Increased D-alanylation of lipoteichoic acid and a thickened septum are main determinants in the nisin resistance mechanism of Lactococcus lactis

¹ Molecular Genetics Group, Groningen Biomolecular Sciences and Biotechnology Institute, University of Groningen, PO Box 14, 9750 AA Haren, The Netherlands
² Department of Biochemistry of Membranes, Center for Biomembranes and Lipid Enzymology, Institute of Biomembranes, Utrecht University, Padualaan 8, 3584 CH Utrecht, The Netherlands
³ Eukaryotic Microbiology, Groningen Biomolecular Sciences and Biotechnology Institute, University of Groningen, PO Box 14, 9750 AA Haren, The Netherlands
⁴ European Commission, Joint Research Centre, IHCP, European Centre for the Validation of Alternative Methods, 21020 Ispra, Italy
⁵ NIZO Food Research, Flavour and Natural Ingredients Section, PO Box 20, 6710 BA Ede, The Netherlands

Correspondence
Oscar P. Kuipers
o.p.kuipers{at}rug.nl

Nisin is a post-translationally modified antimicrobial peptide produced by Lactococcus lactis which binds to lipid II in the membrane to form pores and inhibit cell-wall synthesis. A nisin-resistant (Nis^R) strain of L. lactis, which is able to grow at a 75-fold higher nisin concentration than its parent strain, was investigated with respect to changes in the cell wall. Direct binding studies demonstrated that less nisin was able to bind to lipid II in the membranes of L. lactis Nis^R than in the parent strain. In contrast to vancomycin binding, which showed ring-like binding, nisin was observed to bind in patches close to cell-division sites in both the wild-type and the Nis^R strains. Comparison of modifications in lipoteichoic acid of the L. lactis strains revealed an increase in D-alanyl esters and galactose as substituents in L. lactis Nis^R, resulting in a less negatively charged cell wall. Moreover, the cell wall displays significantly increased thickness at the septum. These results indicate that shielding the membrane and thus the lipid II molecule, thereby decreasing abduction of lipid II and subsequent pore-formation, is a major defence mechanism of L. lactis against nisin.

NMR spectra are available with the online version of this paper.