Dataset Information

Chromosomal and Plasmid-Borne Tigecycline Resistance Genes tet(X3) and tet(X4) in Dairy Cows on a Chinese Farm.

ABSTRACT: We isolated 47 Acinetobacter strains carrying tet(X3) and 4 ST767 E. coli strains carrying tet(X4) from 296 rectal swab samples from dairy cows on a Chinese farm. tet(X3) was located on chromosomes or diverse plasmids, and tet(X4) was located on IncFIBκ/FIA(HI1)/X1 nontransferable plasmid. The coexistence of tet(X3) and carbapenemase genes, including bla_OXA-58 and bla_NDM-1, was detected in 9 Acinetobacter spp. These findings suggested that the use of tetracycline and other antibiotics in food production warrants urgent attention.

SUBMITTER: Zhang R

PROVIDER: S-EPMC7577139 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

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Chromosomal and Plasmid-Borne Tigecycline Resistance Genes tet(X3) and tet(X4) in Dairy Cows on a Chinese Farm.

Zhang Rong R Dong Ning N Zeng Yu Y Shen Zhangqi Z Lu Jiayue J Liu Congcong C Huang Zhuo-An ZA Sun Qiaoling Q Cheng Qipeng Q Shu Lingbin L Cai Jiachang J Chan Edward Waichi EW Liu Dejun D Chen Gongxiang G Wang Yang Y Chen Sheng S

Antimicrobial agents and chemotherapy 20201020 11

We isolated 47 Acinetobacter strains carrying tet(X3) and 4 ST767 E. coli strains carrying tet(X4) from 296 rectal swab samples from dairy cows on a Chinese farm. tet(X3) was located on chromosomes or diverse plasmids, and tet(X4) was located on IncFIBκ/FIA(HI1)/X1 nontransferable plasmid. The coexistence of tet(X3) and carbapenemase genes, including blaOXA-58 and blaNDM-1, was detected in 9 Acinetobacter ...[more]

PMID: 32816739

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Project description:BackgroundTigecycline is one of the few last-resort antibiotics for the treatment of carbapenem-resistant Enterobacteriaceae infection, the incidence of which has been rapidly increasing. However, the emergence and spread of tigecycline resistance genes tet(X) (including tet(X3) and tet(X4)) has largely compromised the efficient usage of tetracyclines in the clinical settings.MethodsThe synergistic effect was determined by a checkerboard minimum inhibitory concentration (MIC) assay, a time-killing assay and scanning electron microscopy (SEM) analysis. In-depth mechanisms were defined using an enzyme inhibition assay, western blotting, RT-PCR analysis, molecular dynamics (MD) simulations, biolayer interferometry (BLI) assay and metabolomics analysis.FindingsHerein, our work identified a natural compound, plumbagin, as an effective broad-spectrum inhibitor of Tet(X) (also known as monooxygenase) by simultaneously inhibiting the activity and the production of Tet(X3)/Tet(X4). Plumbagin in combination with tetracyclines showed a synergistic bactericidal effect against Tet(X3)/Tet(X4)-producing bacteria. Mechanistic studies revealed that direct engagement of plumbagin with the catalytic pocket of Tet(X3)/Tet(X4) induced an alternation in its secondary structure to inhibit the activity of these monooxygenases. As a consequence, monotherapy or combination therapy with plumbagin increases the oxidative stress and metabolism in bacteria. Moreover, in a mouse systemic infection model of tet(X4)-positive E. coli, the combination of plumbagin and methacycline exhibited remarkable treatment benefits, as shown by a reduced bacterial load and the alleviation of pathological injury.InterpretationPlumbagin, as an inhibitor of Tet(X3)/Tet(X4), represents a promising lead drug, as well as an adjunct with tetracyclines to treat bacterial infections, especially for extensively drug-resistant bacteria harbouring Tet(X3)/Tet(X4).FundingThe National Natural Science Foundation of China.

Project description:The emergence of the tet(X) gene is a severe challenge to global public health security, as clinical tigecycline resistance shows a rapidly rising trend. In this research, we identified two tigecycline-resistant Acinetobacter sp. strains containing seven novel tet(X3) variants recovered from fecal samples from Chinese farms. The seven Tet(X3) variants showed 15.4% to 99.7% amino acid identity with Tet(X3). By expressing tet(X3.7) and tet(X3.9), the tigecycline MIC values for Escherichia coli JM109 increased 64-fold (from 0.13 to 8 mg/L). However, the other tet(X3) variants did not have a significant change in the MIC of tigecycline. We found that the 26th amino acid site of Tet(X3.7) changed from proline to serine, and the 25th amino acid site of Tet(X3.9) changed from glycine to alanine, which reduced the MIC of tigecycline by 2-fold [the MIC of tet(X3) to tigecycline was 16 mg/L] but did not affect its expression to tigecycline. The tet(X3) variants surrounded by mobile genetic elements appeared in the structure of gene clusters with tandem repeat sequences and were adjacent to the site-specific recombinase-encoding gene xerD. Therefore, there is a risk of horizontal transfer of resistant genes. Our study reports seven novel tet(X3) variants; the continuing emergence of tigecycline variants makes continuous monitoring of resistance to tigecycline even more critical. IMPORTANCE Although it is illegal to use tigecycline and carbapenems to treat bacterial infections in animals, we can still isolate bacteria containing both mobile resistance genes from animals, and tet(X) is currently an essential factor in degrading tigecycline. Here, we characterized two multidrug-resistant Acinetobacter sp. strains that contained vital resistance genes, such as sul2, a blaOXA-164-like gene, floR, tetM, and multiple novel tet(X3) variants with different tandem structures. It is of paramount significance that their mechanism may transfer to other Gram-negative pathogens, even if their tandem structures have no cumulative effect on tigecycline resistance.

Project description:The emergence of the plasmid-mediated high levels of the tigecycline resistance gene has drawn worldwide attention and has posed a major threat to public health. In this study, we investigated the prevalence of the tet(X4)-positive Enterobacterales isolates collected from a pig slaughterhouse and farms. A total of 101 tigecycline resistance strains were isolated from 353 samples via a medium with tigecycline, of which 33 carried tet(X4) (9.35%, 33/353) and 2 carried tet(X6) (0.57%, 2/353). These strains belong to seven different species, with Escherichia coli being the main host bacteria. Importantly, this report is the first one to demonstrate that tet(X4) was observed in Morganella morganii. Whole-genome sequencing results revealed that tet(X4)-positive bacteria can coexist with other resistance genes, such as blaNDM-1 and cfr. Additionally, we were the first to report that tet(X4) and blaNDM-1 coexist in a Klebsiella quasipneumoniae strain. The phylogenetic tree of 533 tet(X4)-positive E. coli strains was constructed using 509 strains from the NCBI genome assembly database and 24 strains from this study, which arose from 8 sources and belonged to 135 sequence types (STs) worldwide. We used Nanopore sequencing to interpret the selected 21 nonclonal and representative strains and observed that 19 tet(X4)-harboring plasmids were classified into 8 replicon types, and 2 tet(X6) genes were located on integrating conjugative elements. A total of 68.42% of plasmids carrying tet(X4) were transferred successfully with a conjugation frequency of 10-2 to 10-7. These findings highlight that diverse plasmids drive the widespread dissemination of the tigecycline resistance gene tet(X4) in Enterobacterales of porcine origin. IMPORTANCE Tigecycline is considered to be the last resort of defense against diseases caused by broad-spectrum resistant Gram-negative bacteria. In this study, we systematically analyzed the prevalence and genetic environments of the resistance gene tet(X4) in a pig slaughterhouse and farms and the evolutionary relationship of 533 tet(X4)-positive Escherichia coli strains, including 509 tet(X4)-positive E. coli strains selected from the 27,802 assembled genomes of E. coli from the NCBI between 2002 and 2022. The drug resistance of tigecycline is widely prevalent in pig farms where tetracycline is used as a veterinary drug. This prevalence suggests that pigs are a large reservoir of tet(X4) and that tet(X4) can spread horizontally through the food chain via mobile genetic elements. Furthermore, tetracycline resistance may drive tigecycline resistance through some mechanisms. Therefore, it is important to monitor tigecycline resistance, develop effective control measures, and focus on tetracycline use in the pig farms.

Dataset Information

Chromosomal and Plasmid-Borne Tigecycline Resistance Genes tet(X3) and tet(X4) in Dairy Cows on a Chinese Farm.

Publications

Chromosomal and Plasmid-Borne Tigecycline Resistance Genes <i>tet</i>(X3) and <i>tet</i>(X4) in Dairy Cows on a Chinese Farm.

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