The Journal of Experimental Medicine
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Published online 7 May 2001.
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© The Rockefeller University Press, 0022-1007/2001/5/1067/ $5.00
The Journal of Experimental Medicine, Volume 193, Number 9, May 7, 2001 1067-1076

Original Article

Staphylococcus aureus Resistance to Human Defensins and Evasion of Neutrophil Killing via the Novel Virulence Factor MprF Is Based on Modification of Membrane Lipids with L-Lysine

Andreas Peschela,b, Ralph W. Jackc,d, Michael Ottoa, L. Vincent Collinse, Petra Staubitza, Graeme Nicholsonc, Hubert Kalbacherf, Willem F. Nieuwenhuizeng, Günther Jungc,d, Andrej Tarkowskie, Kok P.M. van Kesselb, and Jos A.G. van Strijpb
a Microbial Genetics, University of Tuebingen, 72076 Tuebingen, Germany
b Eijkman Winkler Institute, University Medical Center Utrecht, 3584 CX Utrecht, The Netherlands
c Organic Chemistry, University of Tuebingen, 72076 Tuebingen, Germany
d EMC Microcollections®, 72070 Tuebingen, Germany
e Department of Rheumatology, University of Goeteborg, S-41346 Goeteborg, Sweden
f Medical and Natural Sciences Research Center, University of Tuebingen, 72074 Tuebingen, Germany
g TNO Nutrition and Food Research, 3700 AJ Zeist, The Netherlands

Correspondence to: Andreas Peschel, Microbial Genetics, University of Tuebingen, Auf der Morgenstelle 28E, 72076 Tuebingen, Germany. Tel:49-7071-297-2611 Fax:49-7071-29-5065 E-mail:andreas.peschel{at}uni-tuebingen.de.

Defensins, antimicrobial peptides of the innate immune system, protect human mucosal epithelia and skin against microbial infections and are produced in large amounts by neutrophils. The bacterial pathogen Staphylococcus aureus is insensitive to defensins by virtue of an unknown resistance mechanism. We describe a novel staphylococcal gene, mprF, which determines resistance to several host defense peptides such as defensins and protegrins. An mprF mutant strain was killed considerably faster by human neutrophils and exhibited attenuated virulence in mice, indicating a key role for defensin resistance in the pathogenicity of S. aureus. Analysis of membrane lipids demonstrated that the mprF mutant no longer modifies phosphatidylglycerol with L-lysine. As this unusual modification leads to a reduced negative charge of the membrane surface, MprF-mediated peptide resistance is most likely based on repulsion of the cationic peptides. Accordingly, inactivation of mprF led to increased binding of antimicrobial peptides by the bacteria. MprF has no similarity with genes of known function, but related genes were identified in the genomes of several pathogens including Mycobacterium tuberculosis, Pseudomonas aeruginosa, and Enterococcus faecalis. MprF thus constitutes a novel virulence factor, which may be of general relevance for bacterial pathogens and represents a new target for attacking multidrug resistant bacteria.

Key Words: host defense peptides, oxygen-independent killing, Staphylococcus aureus virulence, phospholipids, innate immunity


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