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Molecular epidemiology and mechanism of Klebsiella pneumoniae resistance to ertapenem but not to other carbapenems in China

Resistance to only ertapenem is an unusual phenotype of carbapenem-resistant Klebsiella pneumoniae (CRKP). This study aimed to investigate the molecular epidemiology and underlying mechanism involved in ertapenem resistance of K. pneumoniae strains that are susceptible to meropenem and imipenem. Amo...

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Autores principales: Wang, Dongliang, Wang, Minggui, He, Tianpeng, Li, Dan, Zhang, Liqin, Zhang, Dongquan, Feng, Junshuai, Yang, Wenli, Yuan, Yuan
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9678918/
https://www.ncbi.nlm.nih.gov/pubmed/36425030
http://dx.doi.org/10.3389/fmicb.2022.974990
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author Wang, Dongliang
Wang, Minggui
He, Tianpeng
Li, Dan
Zhang, Liqin
Zhang, Dongquan
Feng, Junshuai
Yang, Wenli
Yuan, Yuan
author_facet Wang, Dongliang
Wang, Minggui
He, Tianpeng
Li, Dan
Zhang, Liqin
Zhang, Dongquan
Feng, Junshuai
Yang, Wenli
Yuan, Yuan
author_sort Wang, Dongliang
collection PubMed
description Resistance to only ertapenem is an unusual phenotype of carbapenem-resistant Klebsiella pneumoniae (CRKP). This study aimed to investigate the molecular epidemiology and underlying mechanism involved in ertapenem resistance of K. pneumoniae strains that are susceptible to meropenem and imipenem. Among the 697 K. pneumoniae strains isolated from 11 grade A hospitals in China, 245 were CRKP strains, of which 18 strains resistant only to ertapenem were isolated. The genotypes, phenotypes, drug resistance homology, and drug sensitivity were analyzed; moreover, the expressions of efflux pump components and outer membrane proteins were assessed. The whole genomes of these 18 strains were sequenced and analyzed for mutations leading to drug resistance. The results revealed that ertapenem resistance may be related to ramR mutation. The function of ramR was confirmed using gene complementation to the original strain to determine the mechanism underlying ertapenem resistance of K. pneumoniae strains. In total, 7.4% of the tested CRKP strains were resistant only to ertapenem. None of these strains contained carbapenemase genes. Of the 18 ertapenem-resistant strains, 17 expressed the efflux pump, and outer membrane protein expression was reduced or absent in 4 strains. Whole-genome sequencing revealed the presence of mutations that introduced premature ramR codons stop in 14 strains (77.78%). When a functional copy of ramR was restored in the 14 strains, the minimum inhibitory concentration of ertapenem decreased, inhibition of efflux pumps was not detected, and the expression of outer membrane protein OmpK35 was either increased or was restored. These findings reveal the existence of ertapenem-resistant K. pneumoniae exhibiting no clonal transmission between strains. Mutations in ramR were demonstrated to cause outer membrane protein OmpK35 inhibition and over-expression of efflux pump in some strains, which is implicated in ertapenem resistance only in K. pneumoniae.
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spelling pubmed-96789182022-11-23 Molecular epidemiology and mechanism of Klebsiella pneumoniae resistance to ertapenem but not to other carbapenems in China Wang, Dongliang Wang, Minggui He, Tianpeng Li, Dan Zhang, Liqin Zhang, Dongquan Feng, Junshuai Yang, Wenli Yuan, Yuan Front Microbiol Microbiology Resistance to only ertapenem is an unusual phenotype of carbapenem-resistant Klebsiella pneumoniae (CRKP). This study aimed to investigate the molecular epidemiology and underlying mechanism involved in ertapenem resistance of K. pneumoniae strains that are susceptible to meropenem and imipenem. Among the 697 K. pneumoniae strains isolated from 11 grade A hospitals in China, 245 were CRKP strains, of which 18 strains resistant only to ertapenem were isolated. The genotypes, phenotypes, drug resistance homology, and drug sensitivity were analyzed; moreover, the expressions of efflux pump components and outer membrane proteins were assessed. The whole genomes of these 18 strains were sequenced and analyzed for mutations leading to drug resistance. The results revealed that ertapenem resistance may be related to ramR mutation. The function of ramR was confirmed using gene complementation to the original strain to determine the mechanism underlying ertapenem resistance of K. pneumoniae strains. In total, 7.4% of the tested CRKP strains were resistant only to ertapenem. None of these strains contained carbapenemase genes. Of the 18 ertapenem-resistant strains, 17 expressed the efflux pump, and outer membrane protein expression was reduced or absent in 4 strains. Whole-genome sequencing revealed the presence of mutations that introduced premature ramR codons stop in 14 strains (77.78%). When a functional copy of ramR was restored in the 14 strains, the minimum inhibitory concentration of ertapenem decreased, inhibition of efflux pumps was not detected, and the expression of outer membrane protein OmpK35 was either increased or was restored. These findings reveal the existence of ertapenem-resistant K. pneumoniae exhibiting no clonal transmission between strains. Mutations in ramR were demonstrated to cause outer membrane protein OmpK35 inhibition and over-expression of efflux pump in some strains, which is implicated in ertapenem resistance only in K. pneumoniae. Frontiers Media S.A. 2022-11-08 /pmc/articles/PMC9678918/ /pubmed/36425030 http://dx.doi.org/10.3389/fmicb.2022.974990 Text en Copyright © 2022 Wang, Wang, He, Li, Zhang, Zhang, Feng, Yang and Yuan. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Microbiology
Wang, Dongliang
Wang, Minggui
He, Tianpeng
Li, Dan
Zhang, Liqin
Zhang, Dongquan
Feng, Junshuai
Yang, Wenli
Yuan, Yuan
Molecular epidemiology and mechanism of Klebsiella pneumoniae resistance to ertapenem but not to other carbapenems in China
title Molecular epidemiology and mechanism of Klebsiella pneumoniae resistance to ertapenem but not to other carbapenems in China
title_full Molecular epidemiology and mechanism of Klebsiella pneumoniae resistance to ertapenem but not to other carbapenems in China
title_fullStr Molecular epidemiology and mechanism of Klebsiella pneumoniae resistance to ertapenem but not to other carbapenems in China
title_full_unstemmed Molecular epidemiology and mechanism of Klebsiella pneumoniae resistance to ertapenem but not to other carbapenems in China
title_short Molecular epidemiology and mechanism of Klebsiella pneumoniae resistance to ertapenem but not to other carbapenems in China
title_sort molecular epidemiology and mechanism of klebsiella pneumoniae resistance to ertapenem but not to other carbapenems in china
topic Microbiology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9678918/
https://www.ncbi.nlm.nih.gov/pubmed/36425030
http://dx.doi.org/10.3389/fmicb.2022.974990
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