Dataset Information

The Genetic Structures of an Extensively Drug Resistant (XDR) Klebsiella pneumoniae and Its Plasmids.

ABSTRACT: Multi-, extensively-, and pan-drug resistant bacteria are a threat to our health today, because their wide resistance spectra make their infections difficult to cure. In this work, we isolated an extensively drug resistant (XDR) Klebsiella pneumoniae 2-1 strain from the stool sample of a patient diagnosed of colorectal cancer. K. pneumoniae 2-1 was found to be resistant to all the antibiotics tested except for cefepime, tigecycline, and ceftazidime-avibactam. By sequencing the complete genome of K. pneumoniae 2-1, we found it contains a chromosome of 5.23 Mb and two circular plasmids with the size of 246 and 90 kb. The larger plasmid, pKP21HI1 was found to be a new conjugation-defective plasmid belonging to incompatibility group HI1B and a new sequence type. Further comparative genomics analysis and antimicrobial resistance gene analysis showed that although a great deal of changes took place on the chromosome of K. pneumoniae 2-1 in comparison with the reference genome, the extensively drug resistance phenotype of K. pneumoniae 2-1 is primarily due to the two multidrug resistant plasmids it contains. This work explains the genetic and mechanistic basis of the extensive drug resistance of K. pneumoniae 2-1, and found that plasmids play key roles in the strong antibiotic resistance of bacteria.

SUBMITTER: Li L

PROVIDER: S-EPMC6328971 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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The Genetic Structures of an Extensively Drug Resistant (XDR) Klebsiella pneumoniae and Its Plasmids.

Li Ling L Yu Tao T Ma Yanan Y Yang Zhongjun Z Wang Wenjia W Song Xiaobo X Shen Yu Y Guo Tingting T Kong Jian J Wang Mingyu M Xu Hai H

Frontiers in cellular and infection microbiology 20190104

Multi-, extensively-, and pan-drug resistant bacteria are a threat to our health today, because their wide resistance spectra make their infections difficult to cure. In this work, we isolated an extensively drug resistant (XDR) Klebsiella pneumoniae 2-1 strain from the stool sample of a patient diagnosed of colorectal cancer. K. pneumoniae 2-1 was found to be resistant to all the antibiotics tested except for cefepime, tigecycline, and ceftazidime-avibactam. By sequencing the comp ...[more]

PMID: 30662878

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Project description:Background: Carbapenemase-producing Klebsiella pneumoniae (CP-Kp) poses distinct clinical challenges due to extensively drug resistant (XDR) phenotype, and sequence type (ST) 11 is the most dominant blaKPC-2-bearing CP-Kp clone in China. The purpose of this current retrospective study was to explore the genetic factors associated with the success of XDR CP-Kp ST11 strains circulated in the intensive care unit (ICU) of a Chinese tertiary hospital.Methods: Six ST11 XDR CP-Kp strains were identified between May and December 2014 and validated by minimum inhibitory concentration examination, polymerase chain reaction, and pyrosequencing. The six ST11 XDR CP-Kp, as well as three multi-drug resistant (MDR) and four susceptible strains, were sequenced using single-molecule real-time method. Comprehensively structural and functional analysis based on comparative genomics was performed to identify genomic characteristics of the XDR ST11 CP-Kp strains.Results: We found that ST11 XDR blaKPC-2-bearing CP-Kp strains isolated from inpatients spread in the ICU of the hospital. Functionally, genes associated with information storage and processing of the ST11 XDR CP-Kp strains were more abundant than those of MDR and susceptible strains, especially genes correlative with mobile genetic elements (MGEs) such as transposons and prophages. Structurally, eleven large-scale genetic regions taken for the unique genome in these ST11 XDR CP-Kp strains were identified as MGEs including transposons, integrons, prophages, genomic islands, and integrative and conjugative elements. Three of them were located on plasmids and eight on chromosomes; five of them were with antimicrobial resistance genes and eight with adaptation associated genes. Notably, a new blaKPC-2-bearing ??Tn1721-blaKPC-2 transposon, probably transposed and truncated from ?Tn1721-blaKPC-2 by IS903D and ISKpn8, was identified in all six ST11 XDR CP-Kp strains.Conclusion: Our findings suggested that together with clonal spread, MGEs identified uniquely in the ST11 XDR CP-Kp strains might contribute to their formidable adaptability, which facilitated their widespread dissemination in hospital.

Project description:The ability of extensively drug-resistant (XDR) Klebsiella pneumoniae to rapidly acquire resistance to novel antibiotics is a global concern. Moreover, Klebsiella clonal lineages that successfully combine resistance and hypervirulence have increasingly occurred during the last years. However, the underlying mechanisms of counteracting fitness costs that accompany antibiotic resistance acquisition remain largely unexplored. Here, we investigated whether and how an XDR sequence type (ST)307 K. pneumoniae strain developed resistance against the novel drug combination ceftazidime-avibactam (CAZ-AVI) using experimental evolution. In addition, we performed in vitro and in vivo assays, molecular modeling, and bioinformatics to identify resistance-conferring processes and explore the resulting decrease in fitness and virulence. The subsequent amelioration of the initial costs was also addressed. We demonstrate that distinct mutations of the major nonselective porin OmpK36 caused CAZ-AVI resistance that persists even upon following a second experimental evolution without antibiotic selection pressure and that the Klebsiella strain compensates the resulting fitness and virulence costs. Furthermore, the genomic and transcriptomic analyses suggest the envelope stress response regulator rpoE and associated RpoE-regulated genes as drivers of this compensation. This study verifies the crucial role of OmpK36 in CAZ-AVI resistance and shows the rapid adaptation of a bacterial pathogen to compensate fitness- and virulence-associated resistance costs, which possibly contributes to the emergence of successful clonal lineages. IMPORTANCE Extensively drug-resistant Klebsiella pneumoniae causing major outbreaks and severe infections has become a significant challenge for health care systems worldwide. Rapid resistance development against last-resort therapeutics like ceftazidime-avibactam is a significant driver for the accelerated emergence of such pathogens. Therefore, it is crucial to understand what exactly mediates rapid resistance acquisition and how bacterial pathogens counteract accompanying fitness and virulence costs. By combining bioinformatics with in vitro and in vivo phenotypic approaches, this study revealed the critical role of mutations in a particular porin channel in ceftazidime-avibactam resistance development and a major metabolic regulator for ameliorating fitness and virulence costs. These results highlight underlying mechanisms and contribute to the understanding of factors important for the emergence of successful bacterial pathogens.

Dataset Information

The Genetic Structures of an Extensively Drug Resistant (XDR) Klebsiella pneumoniae and Its Plasmids.

Publications

The Genetic Structures of an Extensively Drug Resistant (XDR) <i>Klebsiella pneumoniae</i> and Its Plasmids.

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