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J Infect Dis. 2015 Apr 15;211(8):1317-25. doi: 10.1093/infdis/jiu602. Epub 2014 Oct 31.

A liaR deletion restores susceptibility to daptomycin and antimicrobial peptides in multidrug-resistant Enterococcus faecalis.

Author information

1
Division of Infectious Diseases, Department of Internal Medicine Molecular Genetics and Antimicrobial Resistance Unit, Universidad El Bosque, Bogota, Colombia.
2
Division of Infectious Diseases, Department of Internal Medicine University of Houston College of Pharmacy.
3
Los Angeles Biomedical Research Institute, Harbor-University of California at Los Angeles Medical Center, Torrance David Geffen School of Medicine, University of California at Los Angeles.
4
Department of Microbiology and Molecular Genetics, The University of Texas Health Science Center at Houston.
5
Division of Infectious Diseases, Department of Internal Medicine Clinica Alemana de Santiago and Universidad del Desarrollo, Chile.
6
Division of Infectious Diseases, Department of Internal Medicine.
7
Division of Infectious Diseases, Department of Internal Medicine Department of Microbiology and Molecular Genetics, The University of Texas Health Science Center at Houston.
8
Department of Biochemistry and Cell Biology Department of Ecology and Evolutionary Biology, Rice University, Houston, Texas.
9
Division of Infectious Diseases, Department of Internal Medicine Department of Microbiology and Molecular Genetics, The University of Texas Health Science Center at Houston Molecular Genetics and Antimicrobial Resistance Unit, Universidad El Bosque, Bogota, Colombia.

Abstract

Daptomycin is a lipopeptide antibiotic that is used clinically against many gram-positive bacterial pathogens and is considered a key frontline bactericidal antibiotic to treat multidrug-resistant enterococci. Emergence of daptomycin resistance during therapy of serious enterococcal infections is a major clinical issue. In this work, we show that deletion of the gene encoding the response regulator, LiaR (a member of the LiaFSR system that controls cell envelope homeostasis), from daptomycin-resistant Enterococcus faecalis not only reversed resistance to 2 clinically available cell membrane-targeting antimicrobials (daptomycin and telavancin), but also resulted in hypersusceptibility to these antibiotics and to a variety of antimicrobial peptides of diverse origin and with different mechanisms of action. The changes in susceptibility to these antibiotics and antimicrobial peptides correlated with in vivo attenuation in a Caenorhabditis elegans model. Mechanistically, deletion of liaR altered the localization of cardiolipin microdomains in the cell membrane. Our findings suggest that LiaR is a master regulator of the enterococcal cell membrane response to diverse antimicrobial agents and peptides; as such, LiaR represents a novel target to restore the activity of clinically useful antimicrobials against these organisms and, potentially, increase susceptibility to endogenous antimicrobial peptides.

KEYWORDS:

E. faecalis; LiaFSR; antimicrobial peptides; daptomycin

PMID:
25362197
PMCID:
PMC4402337
DOI:
10.1093/infdis/jiu602
[Indexed for MEDLINE]
Free PMC Article

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