Disrupting Membrane Adaptation Restores in Vivo Efficacy of Antibiotics Against Multidrug-Resistant Enterococci and Potentiates Killing by Human Neutrophils

Sandra Rincon, Diana Panesso, William R. Miller, Kavindra Singh, Melissa R. Cruz, Ayesha Khan, An Q. Dinh, Lorena Diaz, Rafael Rios, Yousif Shamoo, Jinnethe Reyes, Truc T. Tran, Danielle A. Garsin, Cesar A. Arias

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

Abstract

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.

Original languageEnglish (US)
Article numberjiz131
Pages (from-to)494-504
Number of pages11
JournalJournal of Infectious Diseases
Volume220
Issue number3
DOIs
StatePublished - Jul 2 2019

Keywords

  • Caenorhabditis elegans
  • LiaR
  • PMNs
  • daptomycin
  • phagocytosis

ASJC Scopus subject areas

  • Immunology and Allergy
  • Infectious Diseases

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