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Whole-Genome Analyses of Enterococcus faecium Isolates with Diverse Daptomycin MICs

Show simple item record Diaz, Lorena Tran, Truc Munita, Jose Miller, William Rincon, Sandra Carvajal, Lina Wollam, Aye Reyes, Jinnethe Panesso, Diana Rojas, Natalia Shamoo, Yousif Murray, Barbara Weinstock, George Arias, Cesar 2017-04-04T15:53:46Z 2017-04-04T15:53:46Z 2014
dc.identifier.citation Antimicrob Agents Chemother. 2014 Aug;58(8):4527-34 es_CL
dc.identifier.uri es_CL
dc.description.abstract Daptomycin (DAP) is a lipopeptide antibiotic frequently used as a "last-resort" antibiotic against vancomycin-resistant Enterococcus faecium (VRE). However, an important limitation for DAP therapy against VRE is the emergence of resistance during therapy. Mutations in regulatory systems involved in cell envelope homeostasis are postulated to be important mediators of DAP resistance in E. faecium. Thus, in order to gain insights into the genetic bases of DAP resistance in E. faecium, we investigated the presence of changes in 43 predicted proteins previously associated with DAP resistance in enterococci and staphylococci using the genomes of 19 E. faecium with different DAP MICs (range, 3 to 48 μg/ml). Bodipy-DAP (BDP-DAP) binding to the cell membrane assays and time-kill curves (DAP alone and with ampicillin) were performed. Genetic changes involving two major pathways were identified: (i) LiaFSR, a regulatory system associated with the cell envelope stress response, and (ii) YycFGHIJ, a system involved in the regulation of cell wall homeostasis. Thr120 → Ala and Trp73 → Cys substitutions in LiaS and LiaR, respectively, were the most common changes identified. DAP bactericidal activity was abolished in the presence of liaFSR or yycFGHIJ mutations regardless of the DAP MIC and was restored in the presence of ampicillin, but only in representatives of the LiaFSR pathway. Reduced binding of BDP-DAP to the cell surface was the predominant finding correlating with resistance in isolates with DAP MICs above the susceptibility breakpoint. Our findings suggest that genotypic information may be crucial to predict response to DAP plus β-lactam combinations and continue to question the DAP breakpoint of 4 μg/ml. es_CL
dc.format.extent 8 es_CL
dc.language.iso en_US es_CL
dc.publisher American Society for Microbiology es_CL
dc.subject Anti-Bacterial Agents/pharmacology es_CL
dc.subject Bacterial Proteins/genetics es_CL
dc.subject Daptomycin/pharmacology es_CL
dc.subject Enterococcus faecium/drug effects es_CL
dc.subject Genes, Regulator es_CL
dc.subject Genome, Bacterial es_CL
dc.title Whole-Genome Analyses of Enterococcus faecium Isolates with Diverse Daptomycin MICs es_CL
dc.type Artículo es_CL

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