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IS26 Veers Genomic Plasticity and Genetic Rearrangement toward Carbapenem Hyperresistance under Sublethal Antibiotics

Multidrug-resistant Gram-negative carriers of Klebsiella pneumoniae carbapenemases (KPCs) often subvert antibiotic therapy due to inadequate sensitivity in laboratory detection. Although unstable gene amplification has been recognized to crucially contribute to underestimation or misestimation of an...

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Autores principales: Wei, Da-Wei, Wong, Nai-Kei, Song, Yuqin, Zhang, Gang, Wang, Chao, Li, Juan, Feng, Jie
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society for Microbiology 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8822349/
https://www.ncbi.nlm.nih.gov/pubmed/35130728
http://dx.doi.org/10.1128/mbio.03340-21
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author Wei, Da-Wei
Wong, Nai-Kei
Song, Yuqin
Zhang, Gang
Wang, Chao
Li, Juan
Feng, Jie
author_facet Wei, Da-Wei
Wong, Nai-Kei
Song, Yuqin
Zhang, Gang
Wang, Chao
Li, Juan
Feng, Jie
author_sort Wei, Da-Wei
collection PubMed
description Multidrug-resistant Gram-negative carriers of Klebsiella pneumoniae carbapenemases (KPCs) often subvert antibiotic therapy due to inadequate sensitivity in laboratory detection. Although unstable gene amplification has been recognized to crucially contribute to underestimation or misestimation of antimicrobial resistance in clinical isolates, the precise mechanisms underlying carbapenem resistance driven by amplification of bla(KPC-2) remain obscure. Here, we reported that IS26-mediated amplification of bla(KPC-2) rapidly and robustly gave rise to carbapenem hyperresistant phenotypes in an Escherichia coli clinical strain following sublethal meropenem or tobramycin preexposure. Intriguingly, IS26 also underpinned amplification of a 47 kb multiple drug resistance (MDR) region encompassing nine antibiotic resistance genes and six IS26 insertion sequences. Tandem-repeat analysis and experimental validation demonstrated that bla(KPC-2) amplification was indeed mediated by IS26, which was further experimentally shown to involve intricate genetic rearrangement. Such gene amplification arose dynamically under antibiotic stress and subsided upon antibiotic withdrawal. Instead of reducing the amplification of the IS26-flanked MDR region, drug combinations in vitro exacerbated it. Our study, thus, provides valuable insights into how dynamic gene amplification processes can precipitously transform resistance status and complicate diagnosis.
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spelling pubmed-88223492022-02-17 IS26 Veers Genomic Plasticity and Genetic Rearrangement toward Carbapenem Hyperresistance under Sublethal Antibiotics Wei, Da-Wei Wong, Nai-Kei Song, Yuqin Zhang, Gang Wang, Chao Li, Juan Feng, Jie mBio Research Article Multidrug-resistant Gram-negative carriers of Klebsiella pneumoniae carbapenemases (KPCs) often subvert antibiotic therapy due to inadequate sensitivity in laboratory detection. Although unstable gene amplification has been recognized to crucially contribute to underestimation or misestimation of antimicrobial resistance in clinical isolates, the precise mechanisms underlying carbapenem resistance driven by amplification of bla(KPC-2) remain obscure. Here, we reported that IS26-mediated amplification of bla(KPC-2) rapidly and robustly gave rise to carbapenem hyperresistant phenotypes in an Escherichia coli clinical strain following sublethal meropenem or tobramycin preexposure. Intriguingly, IS26 also underpinned amplification of a 47 kb multiple drug resistance (MDR) region encompassing nine antibiotic resistance genes and six IS26 insertion sequences. Tandem-repeat analysis and experimental validation demonstrated that bla(KPC-2) amplification was indeed mediated by IS26, which was further experimentally shown to involve intricate genetic rearrangement. Such gene amplification arose dynamically under antibiotic stress and subsided upon antibiotic withdrawal. Instead of reducing the amplification of the IS26-flanked MDR region, drug combinations in vitro exacerbated it. Our study, thus, provides valuable insights into how dynamic gene amplification processes can precipitously transform resistance status and complicate diagnosis. American Society for Microbiology 2022-02-08 /pmc/articles/PMC8822349/ /pubmed/35130728 http://dx.doi.org/10.1128/mbio.03340-21 Text en Copyright © 2022 Wei 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
Wei, Da-Wei
Wong, Nai-Kei
Song, Yuqin
Zhang, Gang
Wang, Chao
Li, Juan
Feng, Jie
IS26 Veers Genomic Plasticity and Genetic Rearrangement toward Carbapenem Hyperresistance under Sublethal Antibiotics
title IS26 Veers Genomic Plasticity and Genetic Rearrangement toward Carbapenem Hyperresistance under Sublethal Antibiotics
title_full IS26 Veers Genomic Plasticity and Genetic Rearrangement toward Carbapenem Hyperresistance under Sublethal Antibiotics
title_fullStr IS26 Veers Genomic Plasticity and Genetic Rearrangement toward Carbapenem Hyperresistance under Sublethal Antibiotics
title_full_unstemmed IS26 Veers Genomic Plasticity and Genetic Rearrangement toward Carbapenem Hyperresistance under Sublethal Antibiotics
title_short IS26 Veers Genomic Plasticity and Genetic Rearrangement toward Carbapenem Hyperresistance under Sublethal Antibiotics
title_sort is26 veers genomic plasticity and genetic rearrangement toward carbapenem hyperresistance under sublethal antibiotics
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8822349/
https://www.ncbi.nlm.nih.gov/pubmed/35130728
http://dx.doi.org/10.1128/mbio.03340-21
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