Genomic epidemiology of animal-derived tigecycline-resistant Escherichia coli across China reveals recent endemic plasmid-encoded tet(X4) gene

Sun, Chengtao; Cui, Mingquan; Zhang, Shan; Liu, Dejun; Fu, Bo; Li, Zekun; Bai, Rina; Wang, Yaxin; Wang, Hejia; Song, Li; Zhang, Chunping; Zhao, Qi; Shen, Jianzhong; Xu, Shaofa; Wu, Congming

doi:10.1038/s42003-020-01148-0

Cited by 48 publications

(60 citation statements)

References 27 publications

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“…The presence of these plasmids makes the dissemination of bla NDM−1 and/or mcr more heterogeneous. It was worth note that the elements mediating the spread of high-level TGC resistance gene tetX4 in E. coli isolates from pig farms in this study shared highly homologous to those reported previously 3,17,31 (Fig. 6D), suggesting the dissemination of tetX4 might be not as heterogeneous as bla NDM and mcr.…”

Section: Discussionsupporting

confidence: 74%

“…To determine the genetic propensity of the MDR/XDR-E. coli isolates to spread into the human sector, the genetic relatedness of the 515 MDR/XDR-E. coli isolates from pig farms in China to 287 publicly available draft genomes of human commensal E. coli (Bioproject no. PRJNA4001047) were investigated 17 . The 802 E. coli isolates were phylogenetically divided into three lineages (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Phylogenetic trees based on whole-genome single nucleotide polymorphisms (WG-SNPs) were generated using Parsnp (version 1.2) software 44 and were visualized using Interactive Tree Of Life (iTOL v.5) 45 . The draft genomes of 287 human commensal E. coli (PRJNA400107) were downloaded from NCBI and included for phylogenetical analysis in this study 17 .…”

Section: Methodsmentioning

confidence: 99%

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Antimicrobial resistance and population genomics of extensively drug resistant Escherichia coli in pig farms in mainland China: a national wide epidemiological and microbiological study

Peng

et al. 2021

Preprint

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Antimicrobial resistance (AMR) is one of the most urgent threats to the global public health, and the expanding use of antimicrobials in food animals is considered as a main reason for the worldwide rapid increasing of AMR. However, AMR in animals in many regions are poorly documented. China is the largest pig-rearing and pork consumption country in the world. In the present study, we identified AMR in pig farms from all provinces (including Tibet and Qinghai) of mainland China by investigation of a common indicator bacterium Escherichia coli from both pigs and the breeding environmental samples. A total of 2693 samples from pigs and environments in 67 pig farms in all 31 provinces of mainland China were collected between 1 October 2018 to 30 September 2019, and a total of 1871 E. coli strains were isolated. By testing the susceptibility of these 1871 E. coli isolates on 28 types of antibiotics that commonly used in both human and veterinary medicine, we found that resistance to tetracycline (96.26%), chloramphenicol (82.04%), moxifloxacin (81.56%), and trimethoprim/sulfamethoxazole (80.38%) were the broad phenotypes among these E. coli isolates from pig farms in China. A proportion of E. coli isolates were resistant to colistin (3.79%), carbapenems (imipenem [2.62%], meropenem [2.30%], ertapenem [2.46%]), and broad-spectrum-cephalosporins (ceftriaxone [29.56%], cefepime [14.00%]). More than 70% of the isolates displayed multidrug-resistant (MDR), and/or extensively drug-resistant (XDR) phenotypes, and MDR/XDR-E. coli was observed in pig farms in all provinces of mainland China. We also systematically revealed the distribution of O-serogroups, sequence types, resistance genes, virulence factors encoding genes, and putative plasmids of MDR/XDR-E. coli in pig farms from different provinces of China, and partially characterized the pathotypes of certain MDR/XDR-E. coli strains. In addition, the genetic transmission basis of the blaNDM, mcr, ESBL-encoding, fluoroquinolone-resistance, and tetX genes were addressed in this study. Most importantly, we suggested a very high genetic propensity of the pig farm-sourced MDR/XDR-E. coli in spreading into humans. To the best of our knowledge, this is the first study on a national scale that the resistance phenotypes and population genomics of E. coli in pig farms in China are revealed. Our data presented herein will help understand the current profile of AMR in pigs and also provide reference for policy formulation of AMR control action in livestock in China.

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Section: Discussionsupporting

confidence: 74%

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Antimicrobial resistance and population genomics of extensively drug resistant Escherichia coli in pig farms in mainland China: a national wide epidemiological and microbiological study

Peng

et al. 2021

Preprint

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“…Among them, Tet(X/X2) exhibited a wide host range and was present in a variety of bacteria, including Bacteroides spp., Delftia spp., Enterobacteriaceae , Riemerella anatipestifer , Parabacteroides spp., etc., while Tet(X4) was occasionally detected in Aeromonas caviae and Acinetobacter spp. ( 17 , 18 ) but mainly found in E. coli ( 9 , 19 , 20 ).…”

Section: Resultsmentioning

confidence: 99%

Evolutionary Trajectory of the Tet(X) Family: Critical Residue Changes towards High-Level Tigecycline Resistance

et al. 2021

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The emergence of the plasmid-mediated high-level tigecycline resistance mechanism Tet(X) threatens the role of tigecycline as the “last-resort” antibiotic in the treatment of infections caused by carbapenem-resistant Gram-negative bacteria. Compared with that of the prototypical Tet(X), the enzymatic activities of Tet(X3) and Tet(X4) were significantly enhanced, correlating with high-level tigecycline resistance, but the underlying mechanisms remain unclear. In this study, we probed the key amino acid changes leading to the enhancement of Tet(X) function and clarified the structural characteristics and evolutionary path of Tet(X) based upon the key residue changes. Through domain exchange and site-directed mutagenesis experiments, we successfully identified five candidate residues mutations (L282S, A339T, D340N, V350I, and K351E), involved in Tet(X2) activity enhancement. Importantly, these 5 residue changes were 100% conserved among all reported high-activity Tet(X) orthologs, Tet(X3) to Tet(X7), suggesting the important role of these residue changes in the molecular evolution of Tet(X). Structural analysis suggested that the mutant residues did not directly participate in the substrate and flavin adenine dinucleotide (FAD) recognition or binding, but indirectly altered the conformational dynamics of the enzyme through the interaction with adjacent residues. Matrix-assisted laser desorption ionization–time of flight mass spectrometry (MALDI-TOF MS) and UV full-wavelength scanning experiments confirmed that each mutation led to an increase in activity without changing the biochemical properties of the Tet(X) enzyme. Further phylogenetic analysis suggested that Riemerella anatipestifer served as an important incubator and a main bridge vector for the resistance enhancement and spread of Tet(X). This study expands the knowledge of the structure and function of Tet(X) and provides insights into the evolutionary relationship between Tet(X) orthologs. IMPORTANCE The newly emerged tigecycline-inactivating enzymes Tet(X3) and Tet(X4), which are associated with high-level tigecycline resistance, demonstrated significantly higher activities in comparison to that of the prototypical Tet(X) enzyme, threatening the clinical efficacy of tigecycline as a last-resort antibiotic to treat multidrug-resistant (MDR) Gram-negative bacterial infections. However, the molecular mechanisms leading to high-level tigecycline resistance remain elusive. Here, we identified 5 key residue changes that lead to enhanced Tet(X) activity through domain swapping and site-directed mutagenesis. Instead of direct involvement with substrate binding or catalysis, these residue changes indirectly alter the conformational dynamics and allosterically affect enzyme activities. These findings further broaden the understanding of the structural characteristics and functional evolution of Tet(X) and provide a basis for the subsequent screening of specific inhibitors and the development of novel tetracycline antibiotics.

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“…All of these 32 tet(X)-positive strains were subsequently identified as E. coli by 16S rRNA sequencing. Several papers have reported the discovery of tet(X4)-carrying E. coli [ [37][38][39], illustrating the fact that E. coli is an important carrier and indicator organism for the spread of tet(X4). Remarkably, two different strains carrying tet(X4) were isolated from each sample among three samples (Table S2), indicating that the tet(X4) gene could spread in the same microbiota.…”

Section: Recognition and Characterization Of Tet(x)-positive Enterobacteralesmentioning

confidence: 99%

Distribution and genomic characterization of tigecycline-resistant tet(X4)-positive Escherichia coli of swine farm origin

Wang

Peng

et al. 2021

Microbial Genomics

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The emergence of plasmid-mediated tigecycline-resistant strains is posing a serious threat to food safety and human health, which has attracted worldwide attention. The tigecycline resistance gene tet(X4) has been found in diverse sources, but the distribution of tet(X4) and its genetic background in the animal farming environment is not fully understood. Thirty-two tet(X)-positive Escherichia coli strains isolated from 159 samples collected from swine farms showed resistance to tigecycline. The tet(X)-positive strains were characterized by antimicrobial susceptibility testing, conjugation assay, PCR, Illumina and long-read Nanopore sequencing, and bioinformatics analysis. A total of 11 different sequence types (STs) were identified and most of them belonged to phylogroup A, except ST641. In total, 196 possible prophage sequences were identified and some of the prophage regions were found to carry resistance genes, including tet(X4). Furthermore, our results showed possible correlations between CRISPR spacer sequences and serotypes or STs. The co-existence of tigecycline-resistant tet(A) variants and tet(X4) complicates the evolution of vital resistance genes in farming environments. Further, four reorganization plasmids carrying tet(X4) were observed, and the formation mechanism mainly involved homologous recombination. These findings contribute significantly to a better understanding of the diversity and complexity of tet(X4)-bearing plasmids, an emerging novel public health concern.

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Genomic epidemiology of animal-derived tigecycline-resistant Escherichia coli across China reveals recent endemic plasmid-encoded tet(X4) gene

Cited by 48 publications

References 27 publications

Antimicrobial resistance and population genomics of extensively drug resistant Escherichia coli in pig farms in mainland China: a national wide epidemiological and microbiological study

Antimicrobial resistance and population genomics of extensively drug resistant Escherichia coli in pig farms in mainland China: a national wide epidemiological and microbiological study

Evolutionary Trajectory of the Tet(X) Family: Critical Residue Changes towards High-Level Tigecycline Resistance

Distribution and genomic characterization of tigecycline-resistant tet(X4)-positive Escherichia coli of swine farm origin

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