PMID- 24867964
OWN - NLM
STAT- MEDLINE
DCOM- 20150904
LR  - 20220321
IS  - 1098-6596 (Electronic)
IS  - 0066-4804 (Print)
IS  - 0066-4804 (Linking)
VI  - 58
IP  - 8
DP  - 2014 Aug
TI  - Whole-genome analyses of Enterococcus faecium isolates with diverse daptomycin 
      MICs.
PG  - 4527-34
LID - 10.1128/AAC.02686-14 [doi]
AB  - Daptomycin (DAP) is a lipopeptide antibiotic frequently used as a "last-resort" 
      antibiotic against vancomycin-resistant Enterococcus faecium (VRE). However, an 
      important limitation for DAP therapy against VRE is the emergence of resistance 
      during therapy. Mutations in regulatory systems involved in cell envelope 
      homeostasis are postulated to be important mediators of DAP resistance in E. 
      faecium. Thus, in order to gain insights into the genetic bases of DAP resistance 
      in E. faecium, we investigated the presence of changes in 43 predicted proteins 
      previously associated with DAP resistance in enterococci and staphylococci using 
      the genomes of 19 E. faecium with different DAP MICs (range, 3 to 48 mug/ml). 
      Bodipy-DAP (BDP-DAP) binding to the cell membrane assays and time-kill curves 
      (DAP alone and with ampicillin) were performed. Genetic changes involving two 
      major pathways were identified: (i) LiaFSR, a regulatory system associated with 
      the cell envelope stress response, and (ii) YycFGHIJ, a system involved in the 
      regulation of cell wall homeostasis. Thr120 --> Ala and Trp73 --> Cys substitutions 
      in LiaS and LiaR, respectively, were the most common changes identified. DAP 
      bactericidal activity was abolished in the presence of liaFSR or yycFGHIJ 
      mutations regardless of the DAP MIC and was restored in the presence of 
      ampicillin, but only in representatives of the LiaFSR pathway. Reduced binding of 
      BDP-DAP to the cell surface was the predominant finding correlating with 
      resistance in isolates with DAP MICs above the susceptibility breakpoint. Our 
      findings suggest that genotypic information may be crucial to predict response to 
      DAP plus beta-lactam combinations and continue to question the DAP breakpoint of 4 
      mug/ml.
CI  - Copyright (c) 2014, American Society for Microbiology. All Rights Reserved.
FAU - Diaz, Lorena
AU  - Diaz L
AD  - Molecular Genetics and Antimicrobial Resistance Unit, Universidad El Bosque, 
      Bogota, Colombia.
FAU - Tran, Truc T
AU  - Tran TT
AD  - Department of Internal Medicine, Division of Infectious Diseases, University of 
      Texas Medical School at Houston, Houston, Texas, USA University of Houston 
      College of Pharmacy, Houston, Texas, USA.
FAU - Munita, Jose M
AU  - Munita JM
AD  - Department of Internal Medicine, Division of Infectious Diseases, University of 
      Texas Medical School at Houston, Houston, Texas, USA Department of Medicine, 
      Clinica Alemana de Santiago, Universidad del Desarrollo, Santiago, Chile.
FAU - Miller, William R
AU  - Miller WR
AD  - Department of Internal Medicine, Division of Infectious Diseases, University of 
      Texas Medical School at Houston, Houston, Texas, USA.
FAU - Rincon, Sandra
AU  - Rincon S
AD  - Molecular Genetics and Antimicrobial Resistance Unit, Universidad El Bosque, 
      Bogota, Colombia.
FAU - Carvajal, Lina P
AU  - Carvajal LP
AD  - Molecular Genetics and Antimicrobial Resistance Unit, Universidad El Bosque, 
      Bogota, Colombia.
FAU - Wollam, Aye
AU  - Wollam A
AD  - The Genome Institute, Washington University at St. Louis, St. Louis, Missouri, 
      USA.
FAU - Reyes, Jinnethe
AU  - Reyes J
AD  - Molecular Genetics and Antimicrobial Resistance Unit, Universidad El Bosque, 
      Bogota, Colombia Department of Internal Medicine, Division of Infectious 
      Diseases, University of Texas Medical School at Houston, Houston, Texas, USA.
FAU - Panesso, Diana
AU  - Panesso D
AD  - Molecular Genetics and Antimicrobial Resistance Unit, Universidad El Bosque, 
      Bogota, Colombia Department of Internal Medicine, Division of Infectious 
      Diseases, University of Texas Medical School at Houston, Houston, Texas, USA.
FAU - Rojas, Natalia L
AU  - Rojas NL
AD  - Molecular Genetics and Antimicrobial Resistance Unit, Universidad El Bosque, 
      Bogota, Colombia.
FAU - Shamoo, Yousif
AU  - Shamoo Y
AD  - Department of Biochemistry and Cell Biology, Rice University, Houston, Texas, 
      USA.
FAU - Murray, Barbara E
AU  - Murray BE
AD  - Department of Internal Medicine, Division of Infectious Diseases, University of 
      Texas Medical School at Houston, Houston, Texas, USA.
FAU - Weinstock, George M
AU  - Weinstock GM
AD  - The Genome Institute, Washington University at St. Louis, St. Louis, Missouri, 
      USA.
FAU - Arias, Cesar A
AU  - Arias CA
AD  - Molecular Genetics and Antimicrobial Resistance Unit, Universidad El Bosque, 
      Bogota, Colombia Department of Internal Medicine, Division of Infectious 
      Diseases, University of Texas Medical School at Houston, Houston, Texas, USA 
      cesar.arias@uth.tmc.edu.
LA  - eng
GR  - R01 AI080714/AI/NIAID NIH HHS/United States
GR  - R01 AI047923/AI/NIAID NIH HHS/United States
GR  - R01AI093749/AI/NIAID NIH HHS/United States
GR  - R01 AI093749/AI/NIAID NIH HHS/United States
GR  - K08 AI113317/AI/NIAID NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20140527
PL  - United States
TA  - Antimicrob Agents Chemother
JT  - Antimicrobial agents and chemotherapy
JID - 0315061
RN  - 0 (4,4-difluoro-4-bora-3a,4a-diaza-s-indacene)
RN  - 0 (Anti-Bacterial Agents)
RN  - 0 (Bacterial Proteins)
RN  - 0 (Boron Compounds)
RN  - 0 (Fluorescent Dyes)
RN  - 6Q205EH1VU (Vancomycin)
RN  - 7C782967RD (Ampicillin)
RN  - NWQ5N31VKK (Daptomycin)
SB  - IM
MH  - Amino Acid Substitution
MH  - Ampicillin/pharmacology
MH  - Anti-Bacterial Agents/*pharmacology
MH  - Bacterial Proteins/*genetics/metabolism
MH  - Boron Compounds
MH  - Cell Membrane/chemistry/drug effects/genetics/metabolism
MH  - Cell Wall/chemistry/drug effects/genetics/metabolism
MH  - Daptomycin/*pharmacology
MH  - Drug Resistance, Multiple, Bacterial/genetics
MH  - Enterococcus faecium/chemistry/*drug effects/genetics/metabolism
MH  - Fluorescent Dyes
MH  - Gene Expression
MH  - *Genes, Regulator
MH  - *Genome, Bacterial
MH  - Microbial Sensitivity Tests
MH  - Vancomycin/pharmacology
MH  - Vancomycin Resistance/genetics
PMC - PMC4136017
EDAT- 2014/05/29 06:00
MHDA- 2015/09/05 06:00
PMCR- 2015/02/01
CRDT- 2014/05/29 06:00
PHST- 2014/05/29 06:00 [entrez]
PHST- 2014/05/29 06:00 [pubmed]
PHST- 2015/09/05 06:00 [medline]
PHST- 2015/02/01 00:00 [pmc-release]
AID - AAC.02686-14 [pii]
AID - 02686-14 [pii]
AID - 10.1128/AAC.02686-14 [doi]
PST - ppublish
SO  - Antimicrob Agents Chemother. 2014 Aug;58(8):4527-34. doi: 10.1128/AAC.02686-14. 
      Epub 2014 May 27.