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Whole-genome analyses of Enterococcus faecium isolates with diverse daptomycin MICs.


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Científica

Tipología

Investigación y estudios

Medio de publicación

Impreso: Artículos de investigación científica o tecnológica T1

Resumen

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.

Autores

Diaz L1, Tran TT2, Munita JM3, Miller WR4, Rincon S1, Carvajal LP1, Wollam A5, Reyes J6, Panesso D6, Rojas NL1, Shamoo Y7, Murray BE4, Weinstock GM5, Arias CA8.

DOI Artículo Digital Whole-genome analyses of Enterococcus fae...ycin MICs.
Fecha de publicación 04 de agosto de 2014
Fecha de aceptación 21 de julio de 2017
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