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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

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Author: Peschel, A. · Jack, R.W. · Otto, M. · Collins, L.V. · Staubitz, P. · Nicholson, G. · Kalbacher, H. · Nieuwenhuizen, W.F. · Jung, G. · Tarkowski, A. · Kessel, K.P.M. van · Strijp, J.A.G. van
Type:article
Date:2001
Source:Journal of Experimental Medicine, 9, 193, 1067-1076
Identifier: 236062
doi: doi:10.1084/jem.193.9.1067
Keywords: Toxicology · Host defense peptides · Innate immunity · Oxygen-independent killing · Phospholipids · Staphylococcus aureus virulence · antibiotic agent · defensin · gallidermin · gramicidin D · gramicidin S · lysine · magainin 2 · melittin · membrane lipid · nisin · phosphatidylglycerol · protegrin · tachyplesin · unclassified drug · virulence factor · virulence factor mprf · animal model · antibiotic resistance · article · bacterial count · bactericidal activity · controlled study · Enterococcus faecalis · female · gene inactivation · mouse · Mycobacterium tuberculosis · neutrophil · nonhuman · nucleotide sequence · pathogenicity · priority journal · Pseudomonas aeruginosa · Staphylococcus aureus · surface charge · alpha-Defensins · Amino Acid Sequence · Animals · Anti-Bacterial Agents · Bacterial Proteins · Base Sequence · Cell Membrane · Defensins · DNA, Bacterial · Drug Resistance, Microbial · Esterification · Genes, Bacterial · Humans · Lysine · Molecular Sequence Data · Neutrophils · Peptides · Phosphatidylglycerols · Staphylococcus aureus · Swine · Virulence

Abstract

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.