[Source: Journal of Infectious Diseases, full page: (LINK). Abstract, edited.]
Disrupting Membrane Adaptation Restores In VivoEfficacy of Antibiotics Against Multidrug-Resistant Enterococci and Potentiates Killing by Human Neutrophils
Sandra Rincon, Diana Panesso, William R Miller, Kavindra V 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
The Journal of Infectious Diseases, jiz131, https://doi.org/10.1093/infdis/jiz131
Published: 02 April 2019
Daptomycin resistance in enterococci is often mediated by the LiaFSR system that orchestrates the cell membrane (CM) stress response. Activation of LiaFSR through the response regulator LiaR generates major changes in CM 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 CM adaptation restores the in vivo activity of daptomycin. The LiaR effect was also seen in a clinical strain of DAP-resistant E. faecium using a murine model of peritonitis. Furthermore, alteration of the CM response increased the ability of human-PMNs to readily clear both E. faecalis and MDR-E. faecium. Our results provide proof-of-concept that targeting the CM adaptive response restore the in vivo activity of antibiotics, prevent resistance and enhance the ability of the innate immune system to kill infecting bacteria.
LiaR, daptomycin, Caenorhabditis elegans, PMNs, phagocytosis
Issue Section: Major Article
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Keywords: Antibiotics; Drugs Resistance; Daptomycin; Enterococcus spp.