title: Differential Effects of Penicillin Binding Protein Deletion on the Susceptibility of Enterococcus faecium to Cationic Peptide Antibiotics.
abstract: Beta-lactam antibiotics sensitize Enterococcus faecium to killing by endogenous antimicrobial peptides (AMPs) of the innate immune system and daptomycin through mechanisms yet to be elucidated. It has been speculated that beta-lactam inactivation of select E. faecium penicillin binding proteins (PBPs) may play a pivotal role in this sensitization process. To characterize the specific PBP inactivation that may be responsible for these phenotypes, we utilized a previously characterized set of E. faecium PBP knockout mutants to determine the effects of such mutations on the activity of daptomycin and the AMP human cathelicidin (LL-37). Enhanced susceptibility to daptomycin was dependent more on a cumulative effect of multiple PBP deletions than on inactivation of any single specific PBP. Selective knockout of PBPZ rendered E. faecium more vulnerable to killing by both recombinant LL-37 and human neutrophils, which produce the antimicrobial peptide in high quantities. Pharmacotherapy targeting multiple PBPs may be used as adjunctive therapy with daptomycin to treat difficult E. faecium infections.
authors.affiliation: Department of Pediatrics, University of California San Diego School of Medicine, La Jolla, California, USA gsakoulas@ucsd.edu.
authors.forename: George
authors.initials: G
authors.lastname: Sakoulas
authors.affiliation: Department of Internal Medicine, University of California San Diego School of Medicine, La Jolla, California, USA.
authors.forename: Monika
authors.initials: M
authors.lastname: Kumaraswamy
authors.affiliation: Department of Biological Sciences, University of California San Diego School of Medicine, La Jolla, California, USA.
authors.forename: Poochit
authors.initials: P
authors.lastname: Nonejuie
authors.affiliation: Anti-Infective Research Laboratory, Eugene Applebaum College of Pharmacy and Health Sciences, School of Medicine, Wayne State University, Detroit, Michigan, USA.
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Werth
authors.affiliation: Anti-Infective Research Laboratory, Eugene Applebaum College of Pharmacy and Health Sciences, School of Medicine, Wayne State University, Detroit, Michigan, USA.
authors.forename: Micahel J
authors.initials: MJ
authors.lastname: Rybak
authors.affiliation: Department of Biological Sciences, University of California San Diego School of Medicine, La Jolla, California, USA.
authors.forename: Joseph
authors.initials: J
authors.lastname: Pogliano
authors.affiliation: Department of Internal Medicine, Warren Alpert Medical School, Brown University, Providence, Rhode Island, USA.
authors.forename: Louis B
authors.initials: LB
authors.lastname: Rice
authors.affiliation: Department of Pediatrics, University of California San Diego School of Medicine, La Jolla, California, USA.
authors.forename: Victor
authors.initials: V
authors.lastname: Nizet
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D023181:Antimicrobial Cationic Peptides / Q000494:pharmacology*; D017576:Daptomycin / Q000494:pharmacology; D016984:Enterococcus faecium / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism*; D008826:Microbial Sensitivity Tests; D046915:Penicillin-Binding Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D000900:Anti-Bacterial Agents; D023181:Antimicrobial Cationic Peptides; D046915:Penicillin-Binding Proteins; D017576:Daptomycin