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

By Andreas Peschel, R. Jack, M. Otto, L. Collins, Petra Staubitz, G. Nicholson, H. Kalbacher, W. Nieuwenhuizen, G. Jung, A. Tarkowski and 2 more. Journal of Experimental Medicine, 2001

819 citations recorded by the source corpus.

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.

Subfields: Infectious Diseases, Microbiology, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/159ee4607f51ce2420728d8842c3e56074a8ae69

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Infectious Diseases

In Microbiology

In Molecular Biology

Citations in the corpus

The interaction between bacteria and bile. (2005, background): “This incorporation may increase the tensile strength of the membranes [197] or may change their fluidity or charge in away that could affect sensitivity to a-defensins and other host defensemolecules [198,199].”
Antimicrobial peptides: pore formers or metabolic inhibitors in bacteria? (2005, background): “LPG is a basic phospholipid formed by the transfer of L -lysine from lysyl-tRNA to phosphatidylglycero”
Rapid Neutrophil Destruction following Phagocytosis of Staphylococcus aureus (2010, background): “], a phenomenon due in part to moderation of the effects of ROS and antimicrobial peptides [ ,”
Mechanisms of Antimicrobial Peptide Action and Resistance (2003, background): “Recent studies have also demonstrated highly regulated antimicrobial resistance mechanisms involving cytoplasmic membrane modification in Gram-positive bacterial pathogens (Peschel et al., 2001).”
Membrane lipid homeostasis in bacteria (2008, background): “This modification decreases the negative charge of the membrane bilayer, which prevents the intercalation of defensins into the bilayer and increases resistance to neutrophil killing and other cationic antimicrobial agents (such as vancomycin”
Antimicrobial peptides: key components of the innate immune system (2012, background): “It has been reported that S. aureus can resist various AMPs by reducing the net charge of the membrane by introduction of cationic residues in the membranes (Peschel et al., 2001).”
APD: the Antimicrobial Peptide Database (2004, background): “This anionic antimicrobial peptide is promising to kill the human b-defensin-resistant Gram-positive bacterium Staphylococcus aureus, which escapes attacks from cationic peptides probably by incorporating positive charges on the membrane surface by adding Lys to lipids (15).”
Pathogenicity and virulence of Staphylococcus aureus (2021, background): “Both the mprF and dlt genes are regulated by a system termed antimicrobial peptide-sensing system (Aps)RSX, also called (Gra)RSX (for gramicidin resistance), that responds to binding of cationic AMPs [129].”
Mechanisms of nisin resistance in Gram-positive bacteria (2013, neutral): “In addition to the dlt operon, a mprF-dependent lysylination of PG also increases net cell surface charge and prevents cationic antimicrobial peptides (AMP) binding (Peschel et al. 2001; Thedieck et al. 2006).”
The co-evolution of host cationic antimicrobial peptides and microbial resistance (2006, background): “aureus uses a similar concept to change the net negative charge of the major membrane lipid phosphatidylglycerol into a net positive charge by modification with L -lysin”
The Genera Staphylococcus and Macrococcus (2006, background): “CAMPs represent an important human defense mechanism, protecting skin and epithelia against invading microorganisms and assisting neutrophils and platelets.”
Defensins: antimicrobial peptides of innate immunity (2003, background): “In Staphylococcus aureus , the disruption of either of the two genes, Dlt or MprF , increases the sensitivity of the bacteria to defensin”
Mechanisms and consequences of bacterial resistance to antimicrobial peptides. (2016, background): “Typhimurium (Fields et al., 1989; Groisman et al., 1992b), E. coli Groisman et al., 1992a), Group A Streptococcus (GAS) (Nizet et al., 001); S. aureus (Peschel et al., 1999, 2001); and Neisseria meninitidis (Tzeng et al., 2005).”
Temporal shifts in the skin microbiome associated with disease flares and treatment in children with atopic dermatitis (2012, background): “These staphylococcal species may share a mutualistic or commensal relationship to enhance common resistance to antimicrobial peptides (Peschel et al. 2001; Sieprawska-Lupa et al. 2004; Lai et al. 2007; Li et al. 2007) or enhance binding to exposed extracellular matrix proteins in inflamed AD skin…”