Staphylococcus aureus resistance to human defensins and evasion of neutrophil killing via the novel virulence factor MprF is based on modification ofmembrane lipids with L-lysine

Defensins, antimicrobial peptides of the innate immune system, protect huma n mucosal epithelia and skin against microbial infections and are produced in large amounts by neutrophils. The bacterial pathogen Staphylococcus aure us is insensitive to defensins by virtue of an unknown resistance mechanism . We describe a novel staphylococcal gene, mprF, which determines resistanc e to several host defense peptides such as defensins and protegrins. An mpr F mutant strain was killed considerably faster by human neutrophils and exh ibited attenuated virulence in mice, indicating a key role for defensin res istance in the pathogenicity of S. aureus. Analysis of membrane lipids demo nstrated that the mprF mutant no longer modifies phosphatidylglycerol with L-lysine. As this unusual modification leads to a reduced negative charge o f the membrane surface, MprF-mediated peptide resistance is most likely bas ed on repulsion of the cationic peptides. Accordingly, inactivation of mprF led to increased binding of antimicrobial peptides by the bacteria. MprF h as no similarity with genes of known function, but related genes were ident ified in the genomes of several pathogens including Mycobacterium tuberculo sis, Pseudomonas aeruginosa, and Enterococcus faecalis. MprF thus constitut es a novel virulence factor, which may be of general relevance for bacteria l pathogens and represents a new targe for attacking multidrug resistant ba cteria.