<i>Staphylococcus aureus</i> Resistance to Human Defensins and Evasion of Neutrophil Killing via the Novel Virulence Factor Mprf Is Based on Modification of Membrane Lipids with <scp>l</scp>-Lysine

TLDR

Defensins are antimicrobial peptides that protect mucosal surfaces and skin, yet Staphylococcus aureus resists them through an as‑yet‑unknown mechanism linked to the novel gene mprF, which has homologs in several other pathogens. The study aims to characterize the novel gene mprF that confers resistance to host defense peptides including defensins and protegrins. MprF modifies phosphatidylglycerol with l‑lysine, reducing the membrane’s negative charge and thereby repelling cationic antimicrobial peptides. An mprF mutant was killed more rapidly by neutrophils, showed reduced virulence in mice, failed to lysine‑modify membrane lipids, bound more antimicrobial peptides, and thus demonstrates that MprF is a key virulence factor and potential target for multidrug‑resistant bacteria.

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.