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. 2024 Apr 15;3:100069. doi: 10.1016/j.soh.2024.100069

Emergence of plasmid-mediated tigecycline resistance tet(X4) gene in Enterobacterales isolated from wild animals in captivity

Lei Lei a,1, Panfeng Xiong a,b,1, Zelin Yan b, Yanyan Zhang b, Yuchen Wu b, Gongxiang Chen b, Houhui Song a,⁎⁎, Rong Zhang b,⁎
PMCID: PMC11262279  PMID: 39077391

Abstract

Background

Over the past few decades, antimicrobial resistance (AMR) has emerged as a global health challenge in human and veterinary medicine. Research on AMR genes in captive wild animals has increased. However, the presence and molecular characteristics of tet(X)-carrying bacteria in these animals remain unknown.

Methods

Eighty-four samples were collected from captive wild animals. tet(X) variants were detected using polymerase chain reaction and the isolates were identified using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. All isolated strains were subjected to antimicrobial susceptibility testing and whole-genome sequencing. The virulence of an Escherichia coli strain carrying enterotoxin genes was assessed using a Galleria mellonella larval model.

Results

We isolated two tet(X4)-positive E. coli strains and one tet(X4)-positive Raoultella ornithinolytica strain. Antimicrobial susceptibility tests revealed that all three tet(X4)-carrying bacteria were sensitive to the 13 tested antimicrobial agents, but exhibited resistance to tigecycline. Notably, one tet(X4)-carrying E. coli strain producing an enterotoxin had a toxic effect on G. mellonella larvae. Whole-genome sequencing analysis showed that the two tet(X4)-carrying E. coli strains had more than 95% similarity to tet(X4)-containing E. coli strains isolated from pigs and humans in China.

Conclusion

The genetic environment of tet(X4) closely resembled that of the plasmid described in previous studies. Our study identified tet(X4)-positive strains in wildlife and provided valuable epidemiological data for monitoring drug resistance. The identification of enterotoxin-producing E. coli strains also highlights the potential risks posed by virulence genes.

Keywords: Wild animal, tet(X4), Enterobacterales, Enterotoxin, Tigecycline resistance, Epidemiology

1. Introduction

The World Health Organization has declared antimicrobial resistance (AMR) as one of the top ten global public health threats. Over the past few decades, AMR has emerged as an urgent global health challenge for both human and veterinary medicine [1]. The presence of multidrug-resistant (MDR) gram-negative bacteria, such as carbapenem-resistant Enterobacterales, extended-spectrum-beta-lactamase-producing Enterobacterales, and colistin-resistant gram-negative bacteria mediated by mobile colistin resistance (MCR), has significantly compromised the efficacy of commonly used antibiotics, including cephalosporins, and the last-resort antibiotics, carbapenems and colistin [[2], [3], [4]]. Tigecycline, which is effective against serious infections caused by MDR gram-negative bacteria, particularly extensively drug-resistant Enterobacterales and Acinetobacter species, has become a last-resort antimicrobial agent [5].

Tigecycline, a third-generation tetracycline antibiotic, exhibits an expanded spectrum of activity against both gram-negative and gram-positive bacteria. However, the discovery in 2019 of plasmid-encoded tet(X3) and tet(X4) genes, which mediate tetracycline-inactivating monooxygenase and confer high levels of tigecycline resistance, has raised public health concerns [6,7]. Subsequently, a range of plasmid-mediated tet(X) variants, from tet(X5) to tet(X22) [8], have been identified worldwide, with tet(X4) being the dominant genotype. Epidemiological investigations have revealed the presence of tet(X4) in bacteria isolated only from humans, livestock, poultry, wild animals, the food production chain, and the environment [[9], [10], [11]]. Additionally, tet(X4) has been detected in Acinetobacter spp. and Enterobacterales, including Escherichia coli, Klebsiella pneumoniae, and Salmonella spp [12]. The widespread presence of tet(X4)-positive bacteria in various countries and regions has significantly increased the associated public health burden. Therefore, investigating the prevalence of tet(X) variants in different animals and environments is important.

Previous studies have revealed that animal husbandry and the food production chain are key transmission routes and reservoirs of tet(X) variants [13]. Food containing AMR bacteria, selective pressure from the use of antimicrobial agents, and contact with animals or environments harboring AMR genes or bacteria are significant pathways for animals and humans to acquire AMR genes or bacteria. While tet(X4) has been identified in farmed animals and the environment, both nationally and internationally, its prevalence in wildlife and zoo animals has seldom been reported [14,15]. Our study focused on the presence and molecular characteristics of tet(X)-carrying bacteria in captive wild animals with the aim of providing epidemiological data on AMR in these animals.

2. Methods

2.1. Sample collection and isolation

Fecal samples were collected from captive wildlife at a zoo in Hangzhou, Zhejiang Province, China, in November 2022. The samples comprised 84 wild animals, including 15 Muntiacus crinifron, 2 Balaerica regulorum, 2 Ciconia boyciana, 11 Grus japonensis, 8 Anthropoides virgo, 7 Phoenicopteridae, 11 Rhinopithecus roxellana, 10 Pan troglodyte, 10 Hylobatidae, and 8 other primates. Except for the crowned cranes and oriental storks, which shared habitats, the other animals were housed in separate enclosures. A matchhead-sized sample was inoculated in 5 mL of Luria–Bertani broth and incubated at 35 °C for 18 to 20 h. The enrichment culture was then grown on China Blue agar containing 2 mg/L tigecycline at 37 °C for 18 to 20 h. The isolates were purified and species identification was performed using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. tet(X1)–tet(X10) genes were detected by polymerase chain reaction.

2.2. Antimicrobial susceptibility testing

All E. coli isolates were subjected to antimicrobial susceptibility testing. The isolates were screened against the following 15 clinical antimicrobial agents: imipenem, ceftazidime-avibactam, meropenem, ertapenem, cefepime, cefmetazole, polymyxin B, ceftazidime, tigecycline, cefotaxime, amikacin, piperacillin-tazobactam, ciprofloxacin, cefoperazone-sulbactam, and aztreonam. The results were interpreted in accordance with the European Committee on Antimicrobial Susceptibility Testing Breakpoints, version 13.0, and the Clinical and Laboratory Standards Institute's Document M100-ED33.

2.3. Whole-genome sequencing analysis

Genomic DNA was extracted and sequenced on a HiSeq X platform (Illumina, San Diego, CA, USA) using a paired-end strategy. The draft genomes were assembled using SPAdes software (http://bioinf.spbau.ru/spades). Sequence types, AMR genes, and virulence genes were identified using ABRicate software (https://github.com/tseemann/abricate). Genomes collected before April 2023 were downloaded for analysis. A phylogenetic tree, comprising strains from captive animals and those available in the NCBI database (http://www.ncbi.nlm.nih.gov/), was generated using Snippy (https://github.com/tseemann/snippy) and IQ-TREE (https://github.com/iqtree/iqtree2) based on core-genome alignments and was visualized using iTOL (https://itol.embl.de/). Contigs containing tet(X4) were examined to determine their Inc type using the PlasmidFinder tool (https://cge.cbs.dtu.dk/services/). Virulence islands were analyzed using the computational tool IslandViewer 4 (http://www.pathogenomics.sfu.ca/islandviewer2/query.php). The genetic environment of tet(X4) and associated pathogenicity islands was explored using the web-based GenBank data visualization and comparison tool GBKviz (https://gbkviz.streamlit.app/) and the utility program Chiplot (https://www.chiplot.online/). In addition to whole-genome sequencing analysis, we compared the plasmid sequences and genetic environments with those of other tet(X4)-containing plasmids to determine their potential sources and transmission routes.

2.4. Galleria mellonella infection model

G. mellonella (G. mellonella) larvae were infected as previously reported to confirm the in vivo virulence of tet(X)- and eltA-containing strains. Bacterial suspensions in the logarithmic growth phase were diluted in sterile physiological saline solution to a concentration of 107 colony-forming units (CFU)/mL. A sterile physiological saline solution served as the negative control, whereas CVCC195 was used as the positive control. A 10 μL volume of the diluted bacterial suspension was injected into the last pro-legs of the larvae and incubated at 37 °C for 72 h. The number of dead larvae that were unresponsive to touch and black in color was recorded at 8, 16, 24, 32, 40, 48, 56, 64, and 72 h. Kaplan–Meier survival curves were generated using Prism version 8.0.2 (GraphPad, San Diego, CA, USA).

3. Results

3.1. Sample collection and isolation

A total of 84 fecal samples were collected from captive wildlife at a zoo in Hangzhou, China, in November 2022. Three tet(X)-positive strains were isolated: two E. coli strains and one Raoultella ornithinolytica strain. All strains carried the tet(X4) gene. One E. coli strain was isolated from a tufted deer and the other from a gibbon, whereas R. ornithinolytica was isolated from chimpanzees.

3.2. Antimicrobial susceptibility profiles

The antimicrobial susceptibility testing results showed that the three tet(X4)-carrying bacteria were sensitive to the tested antimicrobial agents, but displayed resistance to tigecycline (Table 1). Specifically, the tet(X4)-carrying R. ornithinolytica strain, designated 33, was resistant to ciprofloxacin. Additionally, one tet(X4)-carrying E. coli strain, labeled T8, was highly resistant to cefotaxime, whereas the other E. coli strain was sensitive to ciprofloxacin.

Table 1.

Antimicrobial susceptibility profiles of three tet(X4)-carrying bacteria.

ID MIC(μg/mL)
IMP CAV MEM ETP FEP CMZ PB CAZ TGC CTX CIP TZP AK SCF ATM
33 ≤1 ≤8/4 ≤1 ≤2 ≤4 ≤2 ≤0.5 ≤2 ≥4 ≤4 4 ≤8/4 ≤4 ≤8/4 ≤4
9 ≤1 ≤8/4 ≤1 ≤2 ≤4 ≤2 ≤0.5 ≤2 ≥4 ≤4 ≤1 ≤8/4 ≤4 ≤8/4 ≤4
T8 ≤1 ≤8/4 ≤1 ≤2 ≤4 ≤2 ≤0.5 ≤2 ≥4 >128 ≤1 ≤8/4 ≤4 ≤8/4 ≤4
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Abbreviations: MIC, minimal inhibitory concentration; IMP, imipenem; MEM, meropenem; ETP, ertapenem; CMZ, cefmetazole; CAZ, ceftazidime; CTX, cefotaxime; TZP, piperacillin/tazobactam; SCF, cefoperazone/sulbactam; CAV, ceftazidime/avibactam; FEP, cefepime; PB, polymyxin B; TGC, tigecycline; CIP, ciprofloxacin; AK, amikacin; ATM, aztreonam.

3.3. Genetic diversity of tet(X4)-positive strains

We analyzed the genetic diversity of the three tet(X4)-positive strains and compared them to those from the National Center for Biotechnology Information (NCBI) database. Whole-genome sequencing revealed that the two E. coli strains identified in our study were ST195 and ST5420. The tet(X4)-positive R. ornithinolytica strain carried 11 AMR genes, including the rifampin-resistance gene arr-3, the aminoglycoside-resistance genes [aac(6′)-Ib-cr, aadA16 and dfrA27], the beta-lactam-resistance gene (blaPLA1a), the florfenicol-resistance gene (floR), the fosfomycin-resistance gene (fosA), the quinolone-resistance gene (qnrB6), the sulfonamide-resistance gene (sulI), and the tetracycline-resistance genes [tet(A) and tet(X4)]. The two tet(X4)-positive E. coli strains, named 9 and T8, carried 10 and 14 AMR genes, respectively. Both strains harbored the aminoglycoside-resistance genes aadA2 and dfrA12, the beta-lactam-resistance gene blaTEM-1B, the chloramphenicol-resistance gene cmlA, the florfenicol-resistance gene floR, the quinolone-resistance gene qnrS1, the sulfonamide-resistance gene sulIII, and the tetracycline resistance genes tet(A) and tet(X4). However, strain 9 carried lnu(G), while T8 carried aac(3)-IId, aph(3’)-Ia, blaCTX-M-14, lnu(F), and mef(B).

Two isolates, 9 and T8, were analyzed and compared with other tet(X4)-carrying E. coli strains obtained from the NCBI database. These strains originated from various sources, including pigs, cows, humans, chickens, birds, and captive animals (Fig. 1).

Fig. 1.

Fig. 1

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Phylogenetic tree of E. coli strains from captive animals and various origins. In the graphical representation, circles of different colors denote the antimicrobial susceptibility profile of each strain. Furthermore, the size of the circle correlates with the number of resistance genes present in the strain.

Isolate T8 exhibited >95% similarity to 13 pig-origin isolates collected from Jiangsu (n = 9), Guangxi (n = 1), and Sichuan (n = 3). Similarly, isolate 9 showed >95% similarity with two pig isolates from Henan and Jiangsu and one isolate from a urine sample from a patient in Zhejiang Province. AMR gene analysis revealed that the strains isolated from captive animals possessed fewer AMR genes than those from other sources.

3.4. Plasmid sequencing and genetic environment analysis

The tet(X4)-containing sequences were consistent with the partial sequences of plasmids from waterfowl manure (E. coli strain MY1-8 plasmid pSCMY3, accession No. CP122520.1) and pig slaughterhouses (E. coli strain JS1-EC05 plasmid pEC05-X4, accession No. MN436006.1). All genetic contexts of tet(X4) shared the conserved structure estT-tet(X4)-ISCR2-floR (Fig. 2), which is consistent with previous reports. The Inc types identified in the sequences were distinct from those in the tet(X4) contigs. Col(pHAD28) and IncX1 were detected in isolates 9 and T8. Isolate 9 also contained IncFIA/FIB/FII, IncHI1A/HI1B, and IncR.

Fig. 2.

Fig. 2

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Genetic contexts of tet(X4)-carried strains from captive animals. We performed linear comparisons of the genetic architecture surrounding tet(X4) from various sources. The tet(X4) regions in isolates 9 and T8 were compared with sequences from E. coli plasmids pSCMY3 (originating from waterfowl manure) and pEC05-X4 (derived from pigs).

3.5. Utilizing G. mellonella larvae as a model to investigate the virulence of E. coli isolate 9

An analysis of virulence genes revealed that isolate 9 possessed the heat-labile toxin gene eltAB and the heat-stable toxin gene stb, which are responsible for the production of their respective toxins. G. mellonella larvae were used to assess the virulence of this isolate, and the larvae were infected (Fig. 3). These results indicated that isolate 9 caused mortality in G. mellonella larvae at a concentration of 107 CFU/mL, but exhibited less virulence than the standard strain CVCC195, which produces heat-labile toxins.

Fig. 3.

Fig. 3

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Virulence potential of E. coli isolate 9 using a G. mellonella infection model. The horizontal axis of the graph represents the survival time of G. mellonella larvae and the vertical axis indicates the survival percentage (%).

IslandViewer 4 (http://www.pathogenomics.sfu.ca/islandviewer2/query.php) was utilized to identify the pathogenicity island containing the virulence genes eltAB and stb of E. coli isolate 9. The analysis revealed that these virulence genes were located within a single pathogenicity island. Additionally, the regions upstream and downstream of eltAB and stb contained mobile genetic elements, suggesting the potential for the transfer of these virulence genes (Fig. 4). However, the virulence genes eltAB and stb were interspersed with mobile genetic elements, including IS1351, IS1414, IS2, ISEC18, and IS911, which can migrate to different genetic structures.

Fig. 4.

Fig. 4

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Genetic environment of the pathogenicity island in E. coli isolate 9. The different colors are used to denote the distinct genomic features surrounding the enterotoxin genes.

4. Discussion

Tetracyclines are one of the most commonly used classes of antibiotics in veterinary medicine [16]. However, the use of tetracyclines in animals has led to the emergence of tigecycline-resistant bacteria [17]. Consequently, monitoring these resistant strains in animals is crucial for public health [18]. In our study, tet(X4) was found in E. coli strain ST195 isolated from a migratory bird in Zhejiang, and has previously been found in strains from pork and slaughterhouses in Shanghai, Jiangsu, Shanxi, and Guangdong, and in humans [19,20]. E. coli strain ST195 identified in this study is widely distributed in China and warrants significant attention [21]. In addition, a less commonly reported virulent tet(X4)-positive E. coli strain, ST5420, was identified. The emergence of virulent AMR bacteria poses a threat to the clinical treatment of animals. However, there is no definitive evidence to suggest that this strain initially carried virulence or resistance genes, making the control of these strains a continued challenge.

The conserved genetic context of the strains identified in our study was consistent with that of previous studies [22,23]. However, some studies have reported that tet(X4)-carrying plasmids contain numerous mobile elements, such as IS26, IS3000, and IS1, along with other resistance genes, including aadA22, blaTEM-1B, sulI, and dfrA12 [24,25]. To the best of our knowledge, only a limited number of studies have explored structures containing tet(A) and tet(R) [26] isolated from animal food and environmental samples. Additionally, tet(X4) has been found in plasmids with Inc types, such as IncX1, IncFII, IncFIA/FIB, and IncHI1A/HI1B, which are consistent with the Inc types reported in our study [27].

In the tet(X4)-containing E. coli isolate 9, two enterotoxin genes were identified on the same pathogenicity island positioned adjacent to each other. The insertion sequences flanking the stb gene suggested that stb may have been integrated into this pathogenicity island. E. coli isolate 9 exhibited lower virulence than the standard strain CVCC195, which produces only heat-labile toxins. However, the expression levels of these toxins may differ and the factors that influence their expression remain unknown. Translocations between virulence genes can result in the altered expression of virulence genes, but the specific mechanisms involved require detailed investigation [28].

The persistence of AMR in animals poses a challenge to public health and affects clinical therapy [29]. There are few differences in the feeding patterns of farm and zoo animals. In addition to similar activity spaces, captive wild animals in zoos have similar classifications and methods of medication as farm animals. Unlike food-producing animals, zoo animals do not adhere to standard medication practices, and the drug dosage used for captive wild animals is not necessarily lower than that used for farm animals. Research on AMR bacteria isolated from wild animals has increased in recent years [30], and the presence of virulent bacteria carrying AMR genes has been reported [31,32]. Furthermore, AMR bacteria in the environment can transmit plasmids and strains to wild and zoo animals, posing hidden health risks. Therefore, monitoring virulent AMR bacteria is crucial, and the mechanisms of interaction between virulence genes and AMR genes within bacteria warrant further in-depth investigation.

5. Conclusion

The tet(X4) gene was identified in R. ornithinolytica and E. coli strains isolated from captive wild animals. One E. coli strain carrying tet(X4) possessed virulence genes and exhibited virulence potential. This study reported tet(X4)-harboring E. coli and R. ornithinolytica in captive wildlife. The discovery of enterotoxigenic E. coli highlights the potential threat of virulence. Additionally, the genetic structure of tet(X4) was similar to that of human and animal isolates. This study broadens the known host range of tet(X4) and provides new insights for monitoring drug resistance in wildlife. These findings underscore the need for interdisciplinary approaches to address these issues.

Funding

This work was supported by the National Key Research and Development Program of China [grant number: 2022YFD1800403]; National Natural Science Foundation of China [grant number: 82072341].

Authors’ contributions

HS and RZ: Conceptualization. LL and PX: Data curation; and Writing - original draft. LL, ZY, YZ, and CW: Formal analysis. HS and RZ: Writing - review & editing; GC and RZ: Funding acquisition.

Availability of data and materials

The datasets used and/or analyzed in the current study are available from the corresponding author upon reasonable request.

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Acknowledgments

We would like to express our sincere gratitude the staff at the Hangzhou Safari Park for their invaluable contributions to the successful completion of this study.

Contributor Information

Lei Lei, Email: leilei910@zafu.edu.cn.

Panfeng Xiong, Email: xiongpf@stu.zafu.edu.cn.

Zelin Yan, Email: 22218111@zju.edu.cn.

Yanyan Zhang, Email: 12018247@zju.edu.cn.

Yuchen Wu, Email: 12218313@zju.edu.cn.

Gongxiang Chen, Email: chengongxiang@zju.edu.cn.

Houhui Song, Email: songhh@zafu.edu.cn.

Rong Zhang, Email: zhang-rong@zju.edu.cn.

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Data Availability Statement

The datasets used and/or analyzed in the current study are available from the corresponding author upon reasonable request.

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