title: A liaR deletion restores susceptibility to daptomycin and antimicrobial peptides in multidrug-resistant Enterococcus faecalis.
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.
authors.affiliation: Division of Infectious Diseases, Department of Internal Medicine Molecular Genetics and Antimicrobial Resistance Unit, Universidad El Bosque, Bogota, Colombia.
authors.forename: Jinnethe
authors.initials: J
authors.lastname: Reyes
authors.affiliation: Division of Infectious Diseases, Department of Internal Medicine Molecular Genetics and Antimicrobial Resistance Unit, Universidad El Bosque, Bogota, Colombia.
authors.forename: Diana
authors.initials: D
authors.lastname: Panesso
authors.affiliation: Division of Infectious Diseases, Department of Internal Medicine University of Houston College of Pharmacy.
authors.forename: Truc T
authors.initials: TT
authors.lastname: Tran
authors.affiliation: 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.
authors.forename: Nagendra N
authors.initials: NN
authors.lastname: Mishra
authors.affiliation: Department of Microbiology and Molecular Genetics, The University of Texas Health Science Center at Houston.
authors.forename: Melissa R
authors.initials: MR
authors.lastname: Cruz
authors.affiliation: Division of Infectious Diseases, Department of Internal Medicine Clinica Alemana de Santiago and Universidad del Desarrollo, Chile.
authors.forename: Jose M
authors.initials: JM
authors.lastname: Munita
authors.affiliation: Division of Infectious Diseases, Department of Internal Medicine.
authors.forename: Kavindra V
authors.initials: KV
authors.lastname: Singh
authors.affiliation: 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.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Yeaman
authors.affiliation: Division of Infectious Diseases, Department of Internal Medicine Department of Microbiology and Molecular Genetics, The University of Texas Health Science Center at Houston.
authors.forename: Barbara E
authors.initials: BE
authors.lastname: Murray
authors.affiliation: Department of Biochemistry and Cell Biology Department of Ecology and Evolutionary Biology, Rice University, Houston, Texas.
authors.forename: Yousif
authors.initials: Y
authors.lastname: Shamoo
authors.affiliation: Department of Microbiology and Molecular Genetics, The University of Texas Health Science Center at Houston.
authors.forename: Danielle
authors.initials: D
authors.lastname: Garsin
authors.affiliation: 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.
authors.forename: Arnold S
authors.initials: AS
authors.lastname: Bayer
authors.affiliation: 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.
authors.forename: Cesar A
authors.initials: CA
authors.lastname: Arias
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D000890:Anti-Infective Agents / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000235:genetics*; D017173:Caenorhabditis elegans / Q000378:metabolism / Q000382:microbiology; D002308:Cardiolipins / Q000378:metabolism; D002462:Cell Membrane / Q000378:metabolism / Q000382:microbiology; D017576:Daptomycin / Q000494:pharmacology*; D024901:Drug Resistance, Multiple, Bacterial / Q000235:genetics*; D013293:Enterococcus faecalis / Q000187:drug effects* / Q000235:genetics*; D016908:Gram-Positive Bacterial Infections / Q000188:drug therapy / Q000378:metabolism / Q000382:microbiology; D008826:Microbial Sensitivity Tests / Q000379:methods; D010455:Peptides / Q000494:pharmacology*; D017384:Sequence Deletion / Q000235:genetics
chemical_list: D000900:Anti-Bacterial Agents; D000890:Anti-Infective Agents; D001426:Bacterial Proteins; D002308:Cardiolipins; D010455:Peptides; D017576:Daptomycin
keywords: E. faecalis; LiaFSR; antimicrobial peptides; daptomycin