title: Broad-spectrum antimicrobial peptide resistance by MprF-mediated aminoacylation and flipping of phospholipids.
abstract: Bacteria are frequently exposed to cationic antimicrobial peptides (CAMPs) from eukaryotic hosts (host defence peptides) or from prokaryotic competitors (bacteriocins). However, many bacteria, among them most of the major human pathogens, achieve CAMP resistance by MprF, a unique enzyme that modifies anionic phospholipids with l-lysine or l-alanine thereby introducing positive charges into the membrane surface and reducing the affinity for CAMPs. The lysyl or alanyl groups are derived from aminoacyl tRNAs and are usually transferred to phosphatidylglycerol (PG). Recent studies with MprF from Staphylococcus aureus demonstrated that production of Lys-PG only leads to CAMP resistance when an additional flippase domain of MprF is present that translocates Lys-PG and exposes it at the outer leaflet of the membrane. Thus, MprF exerts two specific functions that have hardly been found in other bacterial proteins. MprF proteins are crucial virulence factors of many human pathogens, which recommends them as targets for new anti-virulence drugs. Intriguingly, specific point mutations in mprF cause resistance to the CAMP-like antibiotic daptomycin in a yet unclear way that may involve altered Lys-PG synthesis and/or Lys-PG flipping capacities. Thus, a thorough characterization of MprF domains and functions will help to unravel how bacteria maintain and protect their cytoplasmic membranes.
authors.affiliation: Cellular and Molecular Microbiology Division, Interfaculty Institute of Microbiology and Infection Medicine, University of Tübingen, Elfriede-Aulhorn-Straße 6, 72076 Tübingen, Germany.
authors.forename: Christoph M
authors.initials: CM
authors.lastname: Ernst
authors.forename: Andreas
authors.initials: A
authors.lastname: Peschel
mesh_terms: D000581:Amidohydrolases / Q000235:genetics / Q000378:metabolism; D049148:Aminoacylation; D019881:Aminoacyltransferases / Q000235:genetics / Q000378:metabolism*; D023181:Antimicrobial Cationic Peptides / Q000378:metabolism / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism*; D024881:Drug Resistance, Bacterial; D049294:Phospholipid Transfer Proteins / Q000235:genetics / Q000378:metabolism; D010743:Phospholipids / Q000378:metabolism*; D013211:Staphylococcus aureus / Q000187:drug effects*
chemical_list: D023181:Antimicrobial Cationic Peptides; D001426:Bacterial Proteins; D049294:Phospholipid Transfer Proteins; D010743:Phospholipids; D019881:Aminoacyltransferases; C429146:mprF protein, Staphylococcus aureus; D000581:Amidohydrolases; C019672:aminoacylase I