Resistencia a colistina en enterobacterias zoonóticas

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Resistencia a colistina en enterobacterias zoonóticas

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Title: Resistencia a colistina en enterobacterias zoonóticas
Author: Iglesias Parro, María del Rocío
Abstract: En España, las infecciones por bacterias resistentes a antimicrobianos causan 30 veces más muertes que los accidentes de tráfico. Se prevé que en 2050 sea la primera causa de muerte a nivel mundial. Para el tratamiento es necesario antibióticos “de último recurso”, como la colistina. En 2015, apareció un determinante de resistencia a colistina transferible horizontalmente (mcr-1). La OMS lo estableció como antibiótico de importancia crítica de máxima prioridad y, EMA y AEMPS establecieron directrices limitando su uso en veterinaria. Por ello, el objetivo de esta tesis es estudiar los mecanismos moleculares que disminuyen la susceptibilidad a colistina en enterobacterias zoonóticas. Al analizar 108 cepas resistentes a colistina de origen animal (E.coli (n=80) y S.enterica (n= 28)) y un modelo in vitro de resistencia a colistina en E.coli (n=10), observamos que la resistencia a colistina co-expresa resistencia a polimixina B. En los aislados clínicos, el mecanismo prevalente es mcr-1. Además, en E. coli encontramos los genes mcr-3 (combinado con mcr-1) y mcr-4 (combinado con mcr-1 o polimorfismos en pmrAB). Los aislados clínicos con determinantes mcr presentaron fenotipos estables. Las cepas de S.enterica con polimorfismos en pmrAB o sin determinante descrito fueron inestables. En los aislados in vitro se detectaron nuevos polimorfismos en pmrAB: R81S en pmrA y L14Q, Q99P y V133F en pmrB, cuyo papel en la resistencia a la colistina se evidenció mediante mutagénesis dirigida. Solo CR4 no presenta determinantes de resistencia a colistina previamente descritos, su análisis genómico identificó varios polimorfismos, aunque su identificación requiere futuros análisis.In Spain, infections caused by antimicrobial-resistant bacteria bring out 30 times more deaths than traffic accidents, and it’s expected that in 2050 it will be the first cause of death worldwide. Last resort antibiotics, such as colistin, are necessary for the treatment. In 2015, a horizontally transferable colistin resistance determinant (mcr-1) appeared. The WHO established colistin as a critical antibiotic of great importance and EMA and AEMPS set guidelines that limit the use of colistin in veterinary medicine. Therefore, the main objective of this thesis is to study the mechanisms of colistin resistance in zoonotic enterobacteria. After analyzing 108 colistin-resistant strains of animal origin (80 E.coli’s strains and 28 S.enterica’s strains); and also, an in vitro model of colistin resistance in E.coli (n=10), we observed that colistin resistance is co-expressed resistance to polymyxin B. In clinical isolates the prevailing mechanism is the mcr-1 gene. In addition, in Escherichia coli we found mcr-3 (in combination with mcr-1) and mcr-4 genes (in combination with mcr-1 or polymorphisms in pmrAB). Escherichia coli and Salmonella enterica clinical isolates with mcr-like determinants presented stable phenotypes, whereas Salmonellas’ with polymorphisms in pmrAB were unstable. When performing the directed mutagenesis experiment, we confirmed that the polymorphisms R81S in pmrA, and L14Q, Q99P and V133F in pmrB confer colistin resistance. On the other hand, one of the mutants selected in vitro, CR4, does not present colistin resistant determinants previously described, although its genomic analysis reveals several polymorphisms that require further studies to be confirmed.
URI: http://hdl.handle.net/10662/8565
Date: 2019-01-22


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