Daptomycin resistance in enterococcus faecium can be delayed by disruption of the LiaFSR stress response pathway

Amy G. Prater; Heer H. Mehta; Kathryn Beabout; Adeline Supandy; William R. Miller; Truc T. Tran; Cesar A. Arias; Yousif Shamoo

doi:10.1128/AAC.01317-20

Daptomycin resistance in enterococcus faecium can be delayed by disruption of the LiaFSR stress response pathway

Amy G. Prater, Heer H. Mehta, Kathryn Beabout, Adeline Supandy, William R. Miller, Truc T. Tran, Cesar A. Arias, Yousif Shamoo

Research output: Contribution to journal › Article › peer-review

10 Scopus citations

Abstract

LiaFSR signaling plays a major role in mediating daptomycin (DAP) resistance in enterococci, and the lack of a functional LiaFSR pathway leads to DAP hypersusceptibility. Using in vitro experimental evolution, we evaluated how Enterococcus faecium with a liaR response regulator gene deletion evolved DAP resistance. We found that knocking out LiaFSR signaling significantly delayed the onset of resistance, but resistance could emerge eventually through various alternate mechanisms that were influenced by the environment.

Original language	English (US)
Article number	e01317-20
Journal	Antimicrobial Agents and Chemotherapy
Volume	65
Issue number	4
DOIs	https://doi.org/10.1128/AAC.01317-20
State	Published - Mar 18 2021

Keywords

Antibiotic resistance
Daptomycin
Drug resistance evolution
Enterococcus
Microbial Sensitivity Tests
Gram-Positive Bacterial Infections
Bacterial Proteins/genetics
Daptomycin/pharmacology
Humans
Drug Resistance, Bacterial/genetics
Enterococcus faecium/genetics
Anti-Bacterial Agents/pharmacology

ASJC Scopus subject areas

Pharmacology (medical)
Infectious Diseases
Pharmacology

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10.1128/AAC.01317-20

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title = "Daptomycin resistance in enterococcus faecium can be delayed by disruption of the LiaFSR stress response pathway",

abstract = "LiaFSR signaling plays a major role in mediating daptomycin (DAP) resistance in enterococci, and the lack of a functional LiaFSR pathway leads to DAP hypersusceptibility. Using in vitro experimental evolution, we evaluated how Enterococcus faecium with a liaR response regulator gene deletion evolved DAP resistance. We found that knocking out LiaFSR signaling significantly delayed the onset of resistance, but resistance could emerge eventually through various alternate mechanisms that were influenced by the environment.",

keywords = "Antibiotic resistance, Daptomycin, Drug resistance evolution, Enterococcus, Microbial Sensitivity Tests, Gram-Positive Bacterial Infections, Bacterial Proteins/genetics, Daptomycin/pharmacology, Humans, Drug Resistance, Bacterial/genetics, Enterococcus faecium/genetics, Anti-Bacterial Agents/pharmacology",

author = "Prater, {Amy G.} and Mehta, {Heer H.} and Kathryn Beabout and Adeline Supandy and Miller, {William R.} and Tran, {Truc T.} and Arias, {Cesar A.} and Yousif Shamoo",

note = "Funding Information: This work was supported by National Institutes of Health, National Institute of Allergy and Infectious Diseases grants R01AI080714 to Y.S., K08 AI135093 to W.R. M., K24-AI121296 and R01-AI134637 to C.A.A., and K08-AI113317 to T.T. Funding Information: C.A.A. has received grants from Merck, MeMEd Diagnostics, and Entasis Therapeutics. W.R.M. has received grants from Merck and Entasis Therapeutics and honoraria from Shionogi. Publisher Copyright: {\textcopyright} 2021 American Society for Microbiology. All rights reserved.",

year = "2021",

month = mar,

day = "18",

doi = "10.1128/AAC.01317-20",

language = "English (US)",

volume = "65",

journal = "Antimicrobial Agents and Chemotherapy",

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publisher = "American Society for Microbiology",

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AU - Prater, Amy G.

AU - Mehta, Heer H.

AU - Beabout, Kathryn

AU - Supandy, Adeline

AU - Miller, William R.

AU - Tran, Truc T.

AU - Arias, Cesar A.

AU - Shamoo, Yousif

N1 - Funding Information: This work was supported by National Institutes of Health, National Institute of Allergy and Infectious Diseases grants R01AI080714 to Y.S., K08 AI135093 to W.R. M., K24-AI121296 and R01-AI134637 to C.A.A., and K08-AI113317 to T.T. Funding Information: C.A.A. has received grants from Merck, MeMEd Diagnostics, and Entasis Therapeutics. W.R.M. has received grants from Merck and Entasis Therapeutics and honoraria from Shionogi. Publisher Copyright: © 2021 American Society for Microbiology. All rights reserved.

PY - 2021/3/18

Y1 - 2021/3/18

N2 - LiaFSR signaling plays a major role in mediating daptomycin (DAP) resistance in enterococci, and the lack of a functional LiaFSR pathway leads to DAP hypersusceptibility. Using in vitro experimental evolution, we evaluated how Enterococcus faecium with a liaR response regulator gene deletion evolved DAP resistance. We found that knocking out LiaFSR signaling significantly delayed the onset of resistance, but resistance could emerge eventually through various alternate mechanisms that were influenced by the environment.

AB - LiaFSR signaling plays a major role in mediating daptomycin (DAP) resistance in enterococci, and the lack of a functional LiaFSR pathway leads to DAP hypersusceptibility. Using in vitro experimental evolution, we evaluated how Enterococcus faecium with a liaR response regulator gene deletion evolved DAP resistance. We found that knocking out LiaFSR signaling significantly delayed the onset of resistance, but resistance could emerge eventually through various alternate mechanisms that were influenced by the environment.

KW - Antibiotic resistance

KW - Daptomycin

KW - Drug resistance evolution

KW - Enterococcus

KW - Microbial Sensitivity Tests

KW - Gram-Positive Bacterial Infections

KW - Bacterial Proteins/genetics

KW - Daptomycin/pharmacology

KW - Humans

KW - Drug Resistance, Bacterial/genetics

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KW - Anti-Bacterial Agents/pharmacology

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Daptomycin resistance in enterococcus faecium can be delayed by disruption of the LiaFSR stress response pathway

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