RESUMEN
Extensively drug-resistant Klebsiella pneumoniae (XDR-KP) infections cause high mortality and are disseminating globally. Identifying the genetic basis underpinning resistance allows for rapid diagnosis and treatment. XDR isolates sourced from Greece and Brazil, including 19 polymyxin-resistant and five polymyxin-susceptible strains, were subjected to whole genome sequencing. Seventeen of the 19 polymyxin-resistant isolates harboured variations upstream or within mgrB. The most common mutation identified was an insertion at nucleotide position 75 in mgrB via an ISKpn26-like element in the ST258 lineage and ISKpn13 in one ST11 isolate. Three strains acquired an IS1 element upstream of mgrB and another strain had an ISKpn25 insertion at 133 bp. Other isolates had truncations (C28STOP, Q30STOP) or a missense mutation (D29E) affecting mgrB. Complementation assays revealed all mgrB perturbations contributed to resistance. Missense mutations in phoQ (T281M, G385C) were also found to facilitate resistance. Several variants in phoPQ co-segregating with the ISKpn26-like insertion were identified as potential partial suppressor mutations. Three ST258 samples were found to contain subpopulations with different resistance-conferring mutations, including the ISKpn26-like insertion colonizing with a novel mutation in pmrB (P158R), both confirmed via complementation assays. These findings highlight the broad spectrum of chromosomal modifications which can facilitate and regulate resistance against polymyxins in K. pneumoniae.
Asunto(s)
Cromosomas Bacterianos/genética , ADN Bacteriano/aislamiento & purificación , Farmacorresistencia Bacteriana/genética , Klebsiella pneumoniae/efectos de los fármacos , Polimixinas/farmacología , Antibacterianos/farmacología , Brasil , Colistina/farmacología , ADN Bacteriano/genética , Escherichia coli/efectos de los fármacos , Escherichia coli/genética , Regulación Bacteriana de la Expresión Génica , Biblioteca de Genes , Genes Bacterianos , Variación Genética , Grecia , Klebsiella pneumoniae/genética , Klebsiella pneumoniae/aislamiento & purificación , Pruebas de Sensibilidad Microbiana , Mutación , Análisis de Secuencia de ADNRESUMEN
Extensively drug-resistant Klebsiella pneumoniae (XDR-KP) infections cause high mortality and are disseminating globally. Identifying the genetic basis underpinning resistance allows for rapid diagnosis and treatment. XDR isolates sourced fromGreece and Brazil, including 19 polymyxin-resistant and five polymyxin-susceptible strains, were subjected to whole genomesequencing. Seventeen of the 19 polymyxin-resistant isolates harboured variations upstream or within mgrB. The mostcommon mutation identified was an insertion at nucleotide position 75 in mgrB via an ISKpn26-like element in the ST258lineage and ISKpn13 in one ST11 isolate. Three strains acquired an IS1 element upstream of mgrB and another strain had anISKpn25 insertion at 133 bp...