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Emergence of the Novel Aminoglycoside Acetyltransferase Variant aac(6′)-Ib-D179Y and Acquisition of Colistin Heteroresistance in Carbapenem-Resistant Klebsiella pneumoniae Due to a Disrupting Mutation in the DNA Repair Enzyme MutS
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)...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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American Society for Microbiology
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8534291/ https://www.ncbi.nlm.nih.gov/pubmed/33443109 http://dx.doi.org/10.1128/mBio.01954-20 |
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author | Sato, Toyotaka Wada, Takayuki Nishijima, Suguru Fukushima, Yukari Nakajima, Chie Suzuki, Yasuhiko Takahashi, Satoshi Yokota, Shin-ichi |
author_facet | Sato, Toyotaka Wada, Takayuki Nishijima, Suguru Fukushima, Yukari Nakajima, Chie Suzuki, Yasuhiko Takahashi, Satoshi Yokota, Shin-ichi |
author_sort | Sato, Toyotaka |
collection | PubMed |
description | 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 (SMKP01mutS(A307T)) 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. SMKP01mutS(A307T) 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. |
format | Online Article Text |
id | pubmed-8534291 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | American Society for Microbiology |
record_format | MEDLINE/PubMed |
spelling | pubmed-85342912021-10-27 Emergence of the Novel Aminoglycoside Acetyltransferase Variant aac(6′)-Ib-D179Y and Acquisition of Colistin Heteroresistance in Carbapenem-Resistant Klebsiella pneumoniae Due to a Disrupting Mutation in the DNA Repair Enzyme MutS Sato, Toyotaka Wada, Takayuki Nishijima, Suguru Fukushima, Yukari Nakajima, Chie Suzuki, Yasuhiko Takahashi, Satoshi Yokota, Shin-ichi mBio Research Article 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 (SMKP01mutS(A307T)) 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. SMKP01mutS(A307T) 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. American Society for Microbiology 2020-12-22 /pmc/articles/PMC8534291/ /pubmed/33443109 http://dx.doi.org/10.1128/mBio.01954-20 Text en Copyright © 2020 Sato et al. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Research Article Sato, Toyotaka Wada, Takayuki Nishijima, Suguru Fukushima, Yukari Nakajima, Chie Suzuki, Yasuhiko Takahashi, Satoshi Yokota, Shin-ichi Emergence of the Novel Aminoglycoside Acetyltransferase Variant aac(6′)-Ib-D179Y and Acquisition of Colistin Heteroresistance in Carbapenem-Resistant Klebsiella pneumoniae Due to a Disrupting Mutation in the DNA Repair Enzyme MutS |
title | Emergence of the Novel Aminoglycoside Acetyltransferase Variant aac(6′)-Ib-D179Y and Acquisition of Colistin Heteroresistance in Carbapenem-Resistant Klebsiella pneumoniae Due to a Disrupting Mutation in the DNA Repair Enzyme MutS |
title_full | Emergence of the Novel Aminoglycoside Acetyltransferase Variant aac(6′)-Ib-D179Y and Acquisition of Colistin Heteroresistance in Carbapenem-Resistant Klebsiella pneumoniae Due to a Disrupting Mutation in the DNA Repair Enzyme MutS |
title_fullStr | Emergence of the Novel Aminoglycoside Acetyltransferase Variant aac(6′)-Ib-D179Y and Acquisition of Colistin Heteroresistance in Carbapenem-Resistant Klebsiella pneumoniae Due to a Disrupting Mutation in the DNA Repair Enzyme MutS |
title_full_unstemmed | Emergence of the Novel Aminoglycoside Acetyltransferase Variant aac(6′)-Ib-D179Y and Acquisition of Colistin Heteroresistance in Carbapenem-Resistant Klebsiella pneumoniae Due to a Disrupting Mutation in the DNA Repair Enzyme MutS |
title_short | Emergence of the Novel Aminoglycoside Acetyltransferase Variant aac(6′)-Ib-D179Y and Acquisition of Colistin Heteroresistance in Carbapenem-Resistant Klebsiella pneumoniae Due to a Disrupting Mutation in the DNA Repair Enzyme MutS |
title_sort | emergence of the novel aminoglycoside acetyltransferase variant aac(6′)-ib-d179y and acquisition of colistin heteroresistance in carbapenem-resistant klebsiella pneumoniae due to a disrupting mutation in the dna repair enzyme muts |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8534291/ https://www.ncbi.nlm.nih.gov/pubmed/33443109 http://dx.doi.org/10.1128/mBio.01954-20 |
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