Portal de investigación
Disrupting Membrane Adaptation Restores In Vivo Efficacy of Antibiotics Against Multidrug-Resistant Enterococci and Potentiates Killing by Human Neutrophils
Fecha de publicación:
Autores organización
Autores
- Miller, WR
- Singh, KV
- Cruz, MR
- Khan, A
- Dinh, AQ
- Diaz, L
- Rios, R
- Shamoo, Y
- Tran, TT
- Garsin, DA
- Arias, CA
Grupos de investigación
Resumen
Daptomycin resistance in enterococci is often mediated by the LiaFSR system, which orchestrates the cell membrane stress response. Activation of LiaFSR through the response regulator LiaR generates major changes in cell membrane function and architecture (membrane adaptive response), permitting the organism to survive the antibiotic attack. Here, using a laboratory strain of Enterococcus faecalis, we developed a novel Caenorhabditis elegans model of daptomycin therapy and showed that disrupting LiaR-mediated cell membrane adaptation restores the in vivo activity of daptomycin. The LiaR effect was also seen in a clinical strain of daptomycin-resistant Enterococcus faecium, using a murine model of peritonitis. Furthermore, alteration of the cell membrane response increased the ability of human polymorphonuclear neutrophils to readily clear both E. faecalis and multidrug-resistant E. faecium. Our results provide proof of concept that targeting the cell membrane adaptive response restores the in vivo activity of antibiotics, prevents resistance, and enhances the ability of the innate immune system to kill infecting bacteria. Altering the cell membrane adaptive response in multidrug-resistant enterococci restored the in vivo activity of daptomycin in Caenorhabditis elegans and mouse peritonitis therapeutic models and increased the ability of the innate immune system to clear infecting bacteria.
© The Author(s) 2019. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.
Datos de la publicación
- ISSN/ISSNe:
- 0022-1899, 1537-6613
- Tipo:
- Article
- Páginas:
- 494-504
Journal Of Infectious Diseases Oxford University Press
Citas Recibidas en Web of Science: 3
Citas Recibidas en Scopus: 5
Documentos
- No hay documentos
Filiaciones
Keywords
- LiaR; daptomycin; Caenorhabditis elegans; PMNs; phagocytosis
Proyectos asociados
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Investigador Principal: JINNETHE CRISTINA REYES MANRIQUE
2017
Consorcio de resistencia a carbapenems en Klebsiella pneumoniae y otras enterobacteriaceae (CRACKLE): un estudio de cohorte prospectivo y observacional” en su componente de coordinación clínica. En inglés. Consortium on Resistance Against Carbapenems in Klebsiella pneumoniae and Other Enterobacteriaceae (CRACKLE): a Prospective, Observational Cohort Study (CRACKLE II). Componente clínico. Ultimo año. Nuevo título. Red de organismos multiresistentes MDRO “ARLG MDRO SOUTH &CENTRAL AMERICA”
Investigador Principal: JINNETHE CRISTINA REYES MANRIQUE
UEB-2017-456 . 2017
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Investigador Principal: SANDRA LILIANA RINCON NUÑEZ
UEB-2018-475 . 2018
Dinámicas de colonización e infección por microorganismos multidrogorresistentes en pacientes de hospitales de alta complejidad
Investigador Principal: JINNETHE CRISTINA REYES MANRIQUE
UEB-2018-476 . 2018
Citar la publicación
Rincon S,Panesso D,Miller WR,Singh KV,Cruz MR,Khan A,Dinh AQ,Diaz L,Rios R,Shamoo Y,Reyes J,Tran TT,Garsin DA,Arias CA. Disrupting Membrane Adaptation Restores In Vivo Efficacy of Antibiotics Against Multidrug-Resistant Enterococci and Potentiates Killing by Human Neutrophils. J Infect Dis. 2019. 220. (3):p. 494-504. IF:5,022. (1).