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Antimicrob Agents Chemother. 2015 Oct;59(10):6132-9. doi: 10.1128/AAC.00486-15. Epub 2015 Jul 20.

Differential Effects of Penicillin Binding Protein Deletion on the Susceptibility of Enterococcus faecium to Cationic Peptide Antibiotics.

Author information

  • 1Department of Pediatrics, University of California San Diego School of Medicine, La Jolla, California, USA gsakoulas@ucsd.edu.
  • 2Department of Internal Medicine, University of California San Diego School of Medicine, La Jolla, California, USA.
  • 3Department of Biological Sciences, University of California San Diego School of Medicine, La Jolla, California, USA.
  • 4Anti-Infective Research Laboratory, Eugene Applebaum College of Pharmacy and Health Sciences, School of Medicine, Wayne State University, Detroit, Michigan, USA.
  • 5Department of Internal Medicine, Warren Alpert Medical School, Brown University, Providence, Rhode Island, USA.
  • 6Department of Pediatrics, University of California San Diego School of Medicine, La Jolla, California, USA.

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.

PMID:
26195528
PMCID:
PMC4576044
DOI:
10.1128/AAC.00486-15
[PubMed - indexed for MEDLINE]
Free PMC Article
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