Emergence of the Novel Aminoglycoside Acetyltransferase Variant <italic toggle="yes">aac(6′)-Ib-D179Y</italic> and Acquisition of Colistin Heteroresistance in Carbapenem-Resistant <italic toggle="yes">Klebsiella pneumoniae</italic> Due to a Disrupting Mutation in the DNA Repair Enzyme MutS

ABSTRACT Amikacin and colistin are effective against carbapenem-resistant Klebsiella pneumoniae. In 2017, we successively isolated three carbapenem-resistant K. pneumoniae isolates (ST967) from a patient with chronic renal failure in Japan. The first (SMKP01, sputum, day 0) and second (SMKP02, blood...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Toyotaka Sato, Takayuki Wada, Suguru Nishijima, Yukari Fukushima, Chie Nakajima, Yasuhiko Suzuki, Satoshi Takahashi, Shin-ichi Yokota
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2020
Materias:	antimicrobial resistance mutS qnrB91 aac(6′)-Ib-D179Y amikacin resistance colistin resistance Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/de48a7d2501a48bcb18ba27fc93d5f06
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:de48a7d2501a48bcb18ba27fc93d5f06
record_format	dspace
spelling	oai:doaj.org-article:de48a7d2501a48bcb18ba27fc93d5f062021-11-15T15:55:43ZEmergence of the Novel Aminoglycoside Acetyltransferase Variant <italic toggle="yes">aac(6′)-Ib-D179Y</italic> and Acquisition of Colistin Heteroresistance in Carbapenem-Resistant <italic toggle="yes">Klebsiella pneumoniae</italic> Due to a Disrupting Mutation in the DNA Repair Enzyme MutS10.1128/mBio.01954-202150-7511https://doaj.org/article/de48a7d2501a48bcb18ba27fc93d5f062020-12-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.01954-20https://doaj.org/toc/2150-7511ABSTRACT Amikacin and colistin are effective against carbapenem-resistant Klebsiella pneumoniae. In 2017, we successively isolated three carbapenem-resistant K. pneumoniae isolates (ST967) from a patient with chronic renal failure in Japan. The first (SMKP01, sputum, day 0) and second (SMKP02, blood, day 14) strains were resistant to most antimicrobials tested but still susceptible to amikacin (MICs of 4 and 0.5 mg/liter, respectively) and colistin (MIC of 0.5 mg/liter for both). The third strain (SMKP03, blood, day 51) was not susceptible to amikacin (MIC, 32 mg/liter), and its MIC for colistin varied (0.5 to 8 mg/liter). Whole-genome sequencing of SMKP01 revealed that 17 of 20 antimicrobial resistance genes, including qnrB91 (a novel qnrB2 variant) and aac(6′)-Ib-cr, were located on an 86.9-kb IncFII-IncQ plasmid. The qnrB91 conferred greater fluoroquinolone resistance than qnrB2. SMKP03 aac(6′)-Ib-cr that possessed a gene mutation that resulted in an R102W substitution, namely, aac(6′)-Ib-D179Y, made a greater contribution to amikacin resistance than did aac(6′)-Ib-cr. SMKP03 harbored a nonsense mutation in mutS, which encodes a DNA repair enzyme. Introduction of this mutation into SMKP01 (SMKP01mutSA307T) resulted in a dramatic increase (>58-fold) in the frequency of spontaneous amikacin-resistant mutants relative to SMKP01, and the substantial mutants possessed aac(6′)-Ib-D179Y. SMKP01mutSA307T exhibited an unstable MIC for colistin (0.5 to 8 mg/liter). The results demonstrate that a disruptive mutation in MutS, arising during the clinical course of an infection, created a platform for the acquisition of amikacin nonsusceptibility and colistin heteroresistance in multidrug-resistant K. pneumoniae, mediated by the elevated frequency of spontaneous mutations. IMPORTANCE The emergence of multidrug resistance in pathogens such as Klebsiella pneumoniae is of great clinical concern. Antimicrobial resistance sometimes arises during the course of an infection. Although many studies have reported the emergence of antimicrobial resistance and novel antimicrobial resistance genes in the clinical isolates, the identity of the bacterial factor(s) that generate this emergence is still unclear. We report that a disruptive mutation in MutS, arising during the clinical course of an infection, created a context for the acquisition of colistin resistance and the emergence of a novel variant of the amikacin resistance gene in multidrug-resistant K. pneumoniae via an increase in the frequency of spontaneous mutation. This observation is important for understanding how K. pneumoniae develops multidrug resistance during infection and could potentially lead to new antimicrobial treatments for high-risk pathological microbes.Toyotaka SatoTakayuki WadaSuguru NishijimaYukari FukushimaChie NakajimaYasuhiko SuzukiSatoshi TakahashiShin-ichi YokotaAmerican Society for Microbiologyarticleantimicrobial resistancemutSqnrB91aac(6′)-Ib-D179Yamikacin resistancecolistin resistanceMicrobiologyQR1-502ENmBio, Vol 11, Iss 6 (2020)
institution	DOAJ
collection	DOAJ
language	EN
topic	antimicrobial resistance mutS qnrB91 aac(6′)-Ib-D179Y amikacin resistance colistin resistance Microbiology QR1-502
spellingShingle	antimicrobial resistance mutS qnrB91 aac(6′)-Ib-D179Y amikacin resistance colistin resistance Microbiology QR1-502 Toyotaka Sato Takayuki Wada Suguru Nishijima Yukari Fukushima Chie Nakajima Yasuhiko Suzuki Satoshi Takahashi Shin-ichi Yokota Emergence of the Novel Aminoglycoside Acetyltransferase Variant <italic toggle="yes">aac(6′)-Ib-D179Y</italic> and Acquisition of Colistin Heteroresistance in Carbapenem-Resistant <italic toggle="yes">Klebsiella pneumoniae</italic> Due to a Disrupting Mutation in the DNA Repair Enzyme MutS
description	ABSTRACT Amikacin and colistin are effective against carbapenem-resistant Klebsiella pneumoniae. In 2017, we successively isolated three carbapenem-resistant K. pneumoniae isolates (ST967) from a patient with chronic renal failure in Japan. The first (SMKP01, sputum, day 0) and second (SMKP02, blood, day 14) strains were resistant to most antimicrobials tested but still susceptible to amikacin (MICs of 4 and 0.5 mg/liter, respectively) and colistin (MIC of 0.5 mg/liter for both). The third strain (SMKP03, blood, day 51) was not susceptible to amikacin (MIC, 32 mg/liter), and its MIC for colistin varied (0.5 to 8 mg/liter). Whole-genome sequencing of SMKP01 revealed that 17 of 20 antimicrobial resistance genes, including qnrB91 (a novel qnrB2 variant) and aac(6′)-Ib-cr, were located on an 86.9-kb IncFII-IncQ plasmid. The qnrB91 conferred greater fluoroquinolone resistance than qnrB2. SMKP03 aac(6′)-Ib-cr that possessed a gene mutation that resulted in an R102W substitution, namely, aac(6′)-Ib-D179Y, made a greater contribution to amikacin resistance than did aac(6′)-Ib-cr. SMKP03 harbored a nonsense mutation in mutS, which encodes a DNA repair enzyme. Introduction of this mutation into SMKP01 (SMKP01mutSA307T) resulted in a dramatic increase (>58-fold) in the frequency of spontaneous amikacin-resistant mutants relative to SMKP01, and the substantial mutants possessed aac(6′)-Ib-D179Y. SMKP01mutSA307T exhibited an unstable MIC for colistin (0.5 to 8 mg/liter). The results demonstrate that a disruptive mutation in MutS, arising during the clinical course of an infection, created a platform for the acquisition of amikacin nonsusceptibility and colistin heteroresistance in multidrug-resistant K. pneumoniae, mediated by the elevated frequency of spontaneous mutations. IMPORTANCE The emergence of multidrug resistance in pathogens such as Klebsiella pneumoniae is of great clinical concern. Antimicrobial resistance sometimes arises during the course of an infection. Although many studies have reported the emergence of antimicrobial resistance and novel antimicrobial resistance genes in the clinical isolates, the identity of the bacterial factor(s) that generate this emergence is still unclear. We report that a disruptive mutation in MutS, arising during the clinical course of an infection, created a context for the acquisition of colistin resistance and the emergence of a novel variant of the amikacin resistance gene in multidrug-resistant K. pneumoniae via an increase in the frequency of spontaneous mutation. This observation is important for understanding how K. pneumoniae develops multidrug resistance during infection and could potentially lead to new antimicrobial treatments for high-risk pathological microbes.
format	article
author	Toyotaka Sato Takayuki Wada Suguru Nishijima Yukari Fukushima Chie Nakajima Yasuhiko Suzuki Satoshi Takahashi Shin-ichi Yokota
author_facet	Toyotaka Sato Takayuki Wada Suguru Nishijima Yukari Fukushima Chie Nakajima Yasuhiko Suzuki Satoshi Takahashi Shin-ichi Yokota
author_sort	Toyotaka Sato
title	Emergence of the Novel Aminoglycoside Acetyltransferase Variant <italic toggle="yes">aac(6′)-Ib-D179Y</italic> and Acquisition of Colistin Heteroresistance in Carbapenem-Resistant <italic toggle="yes">Klebsiella pneumoniae</italic> Due to a Disrupting Mutation in the DNA Repair Enzyme MutS
title_short	Emergence of the Novel Aminoglycoside Acetyltransferase Variant <italic toggle="yes">aac(6′)-Ib-D179Y</italic> and Acquisition of Colistin Heteroresistance in Carbapenem-Resistant <italic toggle="yes">Klebsiella pneumoniae</italic> Due to a Disrupting Mutation in the DNA Repair Enzyme MutS
title_full	Emergence of the Novel Aminoglycoside Acetyltransferase Variant <italic toggle="yes">aac(6′)-Ib-D179Y</italic> and Acquisition of Colistin Heteroresistance in Carbapenem-Resistant <italic toggle="yes">Klebsiella pneumoniae</italic> Due to a Disrupting Mutation in the DNA Repair Enzyme MutS
title_fullStr	Emergence of the Novel Aminoglycoside Acetyltransferase Variant <italic toggle="yes">aac(6′)-Ib-D179Y</italic> and Acquisition of Colistin Heteroresistance in Carbapenem-Resistant <italic toggle="yes">Klebsiella pneumoniae</italic> Due to a Disrupting Mutation in the DNA Repair Enzyme MutS
title_full_unstemmed	Emergence of the Novel Aminoglycoside Acetyltransferase Variant <italic toggle="yes">aac(6′)-Ib-D179Y</italic> and Acquisition of Colistin Heteroresistance in Carbapenem-Resistant <italic toggle="yes">Klebsiella pneumoniae</italic> Due to a Disrupting Mutation in the DNA Repair Enzyme MutS
title_sort	emergence of the novel aminoglycoside acetyltransferase variant <italic toggle="yes">aac(6′)-ib-d179y</italic> and acquisition of colistin heteroresistance in carbapenem-resistant <italic toggle="yes">klebsiella pneumoniae</italic> due to a disrupting mutation in the dna repair enzyme muts
publisher	American Society for Microbiology
publishDate	2020
url	https://doaj.org/article/de48a7d2501a48bcb18ba27fc93d5f06
work_keys_str_mv	AT toyotakasato emergenceofthenovelaminoglycosideacetyltransferasevariantitalictoggleyesaac6ibd179yitalicandacquisitionofcolistinheteroresistanceincarbapenemresistantitalictoggleyesklebsiellapneumoniaeitalicduetoadisruptingmutationinthednarepairenzymemuts AT takayukiwada emergenceofthenovelaminoglycosideacetyltransferasevariantitalictoggleyesaac6ibd179yitalicandacquisitionofcolistinheteroresistanceincarbapenemresistantitalictoggleyesklebsiellapneumoniaeitalicduetoadisruptingmutationinthednarepairenzymemuts AT sugurunishijima emergenceofthenovelaminoglycosideacetyltransferasevariantitalictoggleyesaac6ibd179yitalicandacquisitionofcolistinheteroresistanceincarbapenemresistantitalictoggleyesklebsiellapneumoniaeitalicduetoadisruptingmutationinthednarepairenzymemuts AT yukarifukushima emergenceofthenovelaminoglycosideacetyltransferasevariantitalictoggleyesaac6ibd179yitalicandacquisitionofcolistinheteroresistanceincarbapenemresistantitalictoggleyesklebsiellapneumoniaeitalicduetoadisruptingmutationinthednarepairenzymemuts AT chienakajima emergenceofthenovelaminoglycosideacetyltransferasevariantitalictoggleyesaac6ibd179yitalicandacquisitionofcolistinheteroresistanceincarbapenemresistantitalictoggleyesklebsiellapneumoniaeitalicduetoadisruptingmutationinthednarepairenzymemuts AT yasuhikosuzuki emergenceofthenovelaminoglycosideacetyltransferasevariantitalictoggleyesaac6ibd179yitalicandacquisitionofcolistinheteroresistanceincarbapenemresistantitalictoggleyesklebsiellapneumoniaeitalicduetoadisruptingmutationinthednarepairenzymemuts AT satoshitakahashi emergenceofthenovelaminoglycosideacetyltransferasevariantitalictoggleyesaac6ibd179yitalicandacquisitionofcolistinheteroresistanceincarbapenemresistantitalictoggleyesklebsiellapneumoniaeitalicduetoadisruptingmutationinthednarepairenzymemuts AT shinichiyokota emergenceofthenovelaminoglycosideacetyltransferasevariantitalictoggleyesaac6ibd179yitalicandacquisitionofcolistinheteroresistanceincarbapenemresistantitalictoggleyesklebsiellapneumoniaeitalicduetoadisruptingmutationinthednarepairenzymemuts
_version_	1718427184016654336

Emergence of the Novel Aminoglycoside Acetyltransferase Variant <italic toggle="yes">aac(6′)-Ib-D179Y</italic> and Acquisition of Colistin Heteroresistance in Carbapenem-Resistant <italic toggle="yes">Klebsiella pneumoniae</italic> Due to a Disrupting Mutation in the DNA Repair Enzyme MutS

Ejemplares similares