Unveiling the Global Threat: Genomic Insights into Carbapenem-Resistant Salmonella enterica subsp . enterica in Human

Abstract

The misuse of broad-spectrum antibiotics has facilitated the emergence of carbapenem-resistant Salmonella enterica subsp. enterica (CRSE). This study aims to investigate the genomic characteristics and epidemiological patterns of two strains isolated from pediatric patients, along with 21 CRSE strains collected from humans worldwide. The antimicrobial susceptibility tests were detected by the agar microdilution method. Whole-genome sequence of the two CRSE strains was sequenced using the Illumina platform. Acquisition and analysis of WGS data were performed by the NCBI Pathogen Detection Portal, BacWGSTdb 2.0, Salmonella In Silico Typing Resource, and the Center for Genomic Epidemiology. Two S. Typhimurium isolates from children carried the carbapenemase gene bla_NDM-5 and belonged to ST34. The CRSE isolates predominantly contained the carbapenem resistance gene bla_OXA-48 in the United Kingdom and bla_NDM in China. The virulence gene profiles of these isolates were consistent across different regions. Carbapenem-resistant S. Typhimurium and S. Kentucky were predominantly found in China and the United Kingdom, respectively. ST198 strains were prevalent in the United Kingdom, whereas all ST34 strains were identified in China. This investigation underscores the global dissemination of carbapenem-resistant Salmonella in humans, revealing variations in drug resistance, serotypes, and sequence types across different regions. Therefore, the global detection of carbapenem resistance has important guiding significance for controlling its transmission, preventing infection, and clinical treatment.

Keywords

carbapenem resistance global location prevalence

Introduction

Salmonella is an important zoonotic foodborne pathogen of critical importance to food safety and public health that causes gastroenteritis in humans, which can lead to severe diarrhea and death, especially in children.^1–4 Annually, non-typhoidal Salmonella is conservatively estimated to be responsible for approximately 93,757,000 cases of gastroenteritis and 155,000 deaths on a global scale.⁵ The World Health Organization has designated carbapenem-resistant and third-generation cephalosporin-resistant Enterobacterales as critical-priority pathogens on the list of antibiotic-resistant bacteria.⁶ The swift proliferation of multidrug-resistant Enterobacterales poses an escalating public health threat, particularly those species that exhibit resistance to “last-resort” antibacterial agents, including carbapenems, intensifying the challenges in developing effective treatment strategies. Carbapenem-resistant Salmonella enterica subsp. enterica (CRSE) isolates in pediatric populations are infrequently observed in comparison to other members of the Enterobacterales family, including Klebsiella pneumoniae and Escherichia coli. However, in light of the gradual increase in clinical CRSE strains globally, it is essential to implement a longitudinal epidemiological investigation specifically targeting the surveillance of these strains and the mechanisms underlying their drug resistance. Such research is crucial for the effective control and prevention of the dissemination of antimicrobial resistance. Furthermore, this investigation holds significant clinical relevance for the treatment of infections and the guidance of therapeutic interventions.

Therefore, this study investigated the resistance and virulence characteristics of two clinical strains of CRSE isolated from infants and young children at the genetic level. Additionally, it conducted an epidemiological analysis and assessed the drug-resistant properties in comparison with global CRSE strains in human.

Materials and Methods

Bacterial isolates

Two strains of Salmonella isolated from children’s stool were collected at the Children’s Hospital in 2021 and 2023. First, we preliminarily screened the suspected colonies using Salmonella–Shigella agar (Comagal, Shanghai, China), then identified the species using matrix-assisted laser desorption–ionization time-of-flight mass spectrometry (MALDI-TOF MS, Bruker, Germany), and stored them at −80°C. Further identification confirmed the isolates as Salmonella enterica subsp. enterica serovar Typhimurium (S. Typhimurium) using commercial antisera (Tianrun, Ningbo, China) according to the modified Kauffmann–White classification scheme.⁷

Antimicrobial susceptibility test

Inhibition zone diameter of 9 antimicrobial agents, including ampicillin (AMP), piperacillin/tazobactam (TZP), amoxycillin/clavulanic acid (AMC), ampicillin/sulbactam (SAM), ceftriaxone (CRO), imipenem (IPM), ertapenem (ETP), meropenem (MEM), chloramphenicol (C), ciprofloxacin (CIP), trimethoprim-sulfamethoxazole (SXT) to the two S. Typhimurium strains were performed by Kirby–Bauer disk diffusion method in accordance with the latest guidelines established by the Clinical and Laboratory Standards Institute (CLSI). Escherichia coli ATCC 25922 strain was employed as the quality control reference standard.

Genome extraction and sequencing

First, we used blood agar plates to recover the two S. Typhimurium strains for 16–18 hours, and then used QIAGEN DNA miniprep kit (QIAGEN, Hilden, Germany) to extract the DNA of the two Salmonella strains. And the extracted DNA was sent to a sequencing institution (Hangzhou Digital-Micro Biotechnology Co. Ltd.) for sequencing. Whole-genome sequence (WGS) of the two S. Typhimurium strains were sequenced using the Illumina platform. And we trim sequencing reads and assemble them into contigs using Unicycler (https://github.com/tseemann/shovill).

Acquisition and analysis of WGS data

All publicly accessible CRSE genome sequences were systematically downloaded from the NCBI Pathogen Detection Portal on May 24, 2024 (https://www.ncbi.nlm.nih.gov/pathogens). We employed BacWGSTdb 2.0⁸ to conduct multi-locus sequencing typing (MLST), identify antimicrobial resistance genes in the target isolates, and construct a phylogenetic tree based on core genome single-nucleotide polymorphisms (cgSNP) of global CRSE strains. The serotypes of the strains were determined by the Salmonella In Silico Typing Resource (SISTR).⁹ And plasmids were processed and analyzed at the Center for Genomic Epidemiology. (CGE).

Results

Genome characteristics and epidemiology of two isolates from children in China

The two S. Typhimurium strains (21CR6302 and 23CR6032) were isolated from the feces samples of 9-month-old child patient and 10-month-old child patient with acute enteritis in Hangzhou, Zhejiang Province, China, in 2021 and 2023, respectively. The serovar antigen of these two strains was 1,4,[5],12:i:-. According to the MLST classification of Salmonella, both strains belong to sequence type 34 (ST34). Antimicrobial susceptibility test shows strain 21CR6302 was resistant to AMP, TZP, AMC, SAM, CRO, IPM, ETP, MEM, C, CIP, and SXT. And strain 23CR6032 was resistant to AMP, TZP, AMC, SAM, CRO, IPM, ETP, MEM, C. The antimicrobial resistance genes (ARGs) found in strains 21CR6302 and 23CR6032 are presented in FIG. 1., respectively. Twenty-two ARGs were found in 21CR6302. involving the beta-lactam resistance genes bla_NDM-5, bla_OXA-1 and bla_TEM-1B, the aminoglycoside resistance genes aadA1, aadA2, aph(4)-Ia, aac(3)-IV, aac(6’)-Iaa, aac(6’)-Ib-cr, rmtB, aph(6)-Id, aph(3′’)-Ib and aph(3′)-Ia, the sulphonamide resistance genes sul2 and sul3, the phenicol resistance genes cmlA1, floR and catB3, the quinolone resistance gene qnrS2, the rifampicin resistance gene ARR-3, the tetracycline resistance gene tet(B) and the trimethoprim resistance gene dfrA12. Nine ARGs were identified in 23CR6032, including the beta-lactam resistance genes bla_NDM-5, and bla_TEM-1B, the aminoglycoside resistance genes aac(6’)-Iaa, aph(6)-Id, and aph(3′’)-Ib, the sulphonamide resistance genes sul1 and sul2, the phenicol resistance genes floR, and the tetracycline resistance gene tet(B).

FIG. 1.

The phylogenetic relationships and antimicrobial resistance genes among 23 carbapenem-resistant Salmonella enterica subsp. enterica (CRSE) strains retrieved from the NCBI Pathogen Detection Portal were analyzed. As indicated in the figure legend, the strains are differentiated by their geographical origin, sequence type (ST), and serovar. Orange squares denote the presence of resistance genes, while white squares indicate their absence.

Analysis of ARGs carried by CRSE from humans

Analysis of ARGs revealed that 23 CRSE strains were multidrug-resistant strains (Fig. 1). In China, 5 of the seven CRSE strains carried the carbapenem resistance gene bla_NDM-5 (5/7, 71.4%), followed by 2 bla_NDM-1 (2/7, 28.6%). However, in the United Kingdom, 14 CRSE strains mainly carried carbapenem resistance gene bla_OXA-48 (9/14, 64.3%), followed by bla_NDM-1 (5/14, 35.7%). As well as one bla_OXA-48 was found in Singapore and one bla_OXA-48 in South Africa. And elevated resistance rates to Aminoglycosides (23/23, 100%), Sulfamethoxazole (18/23, 78.3%), and Tetracycline (14/23, 60.9%) and a low resistance rate to Quinolone (3/23, 13.0%) were discovered in 23 CRSE strains.

Virulence genes of CRSE from human

The composition of virulence genes of the 23 CRSE strains was indistinguishable in different regions (Supplementary Fig. S1). In China, A total of 115 virulence genes were discovered in strains 21CR6302, 23CR6032, 1722, and S2122, which carried the same virulence genes, including 72 genes of the Secretion System, 34 genes of adherence, 2 genes of enterobactin, 2 genes of magnesium uptake, and 5 other types of genes. And in the United Kingdom, strains 628820, 770104, 231978, 202241, 195756, 305192, and 195737 carried the same virulence genes, including 68 genes of the Secretion System, 33 genes of adherence, 2 genes of enterobactin, 2 genes of magnesium uptake, and 4 other types of genes. And strain GCA_016849585.1 in Singapore carried 66 genes of the Secretion System, 33 genes of adherence, 2 genes of enterobactin, 2 genes of magnesium uptake, and 5 other types of genes. And strain GCA_016025345.1 in South Africa carried 120 virulence genes, 72 genes of the Secretion System, 37 genes of adherence, 2 genes of enterobactin, 2 genes of magnesium uptake, and 7 other types of genes.

Epidemiology of CRSE from human

The phylogenetic relationship among S. Typhimurium 21CR6302 and 23CR6032 and a total of 21 CRSE clinical strains worldwide in the NCBI Pathogen Detection Portal was analyzed using BacWGSTdb 2.0 based on a cgSNP strategy (Fig. 1). We analyzed the characteristics of regions, MLST, and drug resistance genes. Clinical CRSE isolates were mainly found in four regions: the United Kingdom, China, Singapore, and South Africa (Fig. 1). The United Kingdom was the main place of discovery, with a total of 14 strains, followed by 7 in China, one in Singapore, and South Africa. There were 6 main serotypes of strains identified by SISTR: 7 S. enterica subsp. enterica serovar Typhimurium, 7 S. enterica subsp. enterica serovar Kentucky, 4 S. enterica subsp. enterica serovar Senftenberg, 2 S. enterica subsp. enterica serovar London, 2 S. enterica subsp. enterica serovar Kottbus, and one S. enterica subsp. enterica serovar Enteritidis. Carbapenem-resistant S. enterica subsp. enterica serovar Kentucky (7/14, 50%) was the most prevalent in the United Kingdom, while carbapenem-resistant S. enterica subsp. enterica serovar Typhimurium (5/7, 71.4%) was predominantly found in China. And MLST results showed that ST198 (7/23, 30.4%) strains were the most popular clinical CRSE worldwide, which were primarily concentrated in the United Kingdom. Interestingly, all ST34 strains were found in China, and the number of cgSNPs differences among 5 strains from China ranged from 49 to 138 (Supplementary Fig. S2).

Discussion

Foodborne salmonellosis is a major public health problem worldwide. It is estimated that 7.5% of deaths from foodborne illnesses in the United States each year are caused by Salmonella in meat and poultry products, and 22.2% of foodborne illnesses in China are caused by Salmonella.^10,11 Non-typhoidal Salmonella species are among the most prevalent foodborne pathogens, with S. Typhimurium being the most common.¹² Reports indicate that the mortality rate associated with S. Typhimurium infection is three times higher than that of other Salmonella infections, and it exhibits multidrug resistance.¹³ With the growing prevalence of multidrug-resistant Gram-negative bacterial infections, carbapenems have become increasingly recognized as the last-line therapeutic option among antimicrobial agents, are often the preferred choice for treating such infections due to their broad spectrum of activity among β-lactam antibiotics.¹⁴ In this study, two rare CRSE strains were isolated from infants suffering from gastroenteritis. The strains, designated S. Typhimurium 21CR6302 and 23CR6032, exhibit multidrug resistance and harbor the carbapenem-resistant gene bla_NDM-5. The mechanisms of carbapenem-resistant Enterobacterales include production of carbapenemases, outer membrane protein deletion or alteration, overexpression of the efflux pump, altered biofilm components, and penicillin-binding protein alterations.^14,15 Since CRSE isolates were infrequently observed, the resistance mechanisms of CRSE remain poorly understood. It is currently established that plasmid-borne carbapenemases have been identified in Salmonella, such as bla_KPC-2, bla_IMP-4, bla_VIM-2, and bla_OXA-48.^16–20 In addition, Hsu et al. reported that the combination of AmpC β-lactamase and porin deletion decreases susceptibility to imipenem.²¹ Similarly, Armand-Lefèvre et al. demonstrated that the presence of OmpF-immunorelated porin along with CMY-4 β-lactamase production confers resistance to carbapenems in Salmonella enterica Serovar Wien.²² Furthermore, both strains exhibited multidrug resistance to β-lactams, aminoglycosides, sulfonamides, and tetracyclines. It is important to highlight that, aside from exhibiting high sensitivity to quinolones, 23 strains demonstrated substantial resistance to other antimicrobial agents. With the spread and transmission of the abovementioned multidrug-resistant strains, the dilemma of having no cure may occur, especially for children, because quinolones can affect children’s bone development.

It is well-established that Salmonella initially adheres to the intestinal epithelial cells, subsequently invades these cells, and releases a substantial amount of toxins, ultimately leading to disease manifestation. Several key virulence determinants of Salmonella are encoded by genes situated within Salmonella pathogenicity islands (SPIs). To date, five SPIs (SPI-1 to SPI-5) have been identified as being closely associated with the virulence of S. Typhimurium.^2,23 In this study, a total of 72 Secretion System genes (T3SS-related genes mediated by SPI-1 and SPI-2) and 34 adhesion-related genes were identified in the two strains, suggesting that both adhesion and T3SS are critical for the pathogenicity of S. Typhimurium. Enterobactin (Ent; a catecholate siderophore), which is ubiquitously present in Enterobacterales, exhibits a high affinity for iron, enabling it to sequester iron from host iron-binding proteins in S. Typhimurium.^24–26 The genes mgtC and mgtB in S. Typhimurium encode a Mg²⁺ transporter that regulates magnesium ion concentration within the bacteria.²⁷ Additionally, mgtC functions as a virulence factor, playing a crucial role in the survival of the bacteria within macrophages.²⁸ Both Enterobactin and mgtCB played a vital role in the growth and replication of bacteria. mig14 is recognized as one of the earliest identified virulence factors of S. Typhimurium, contributing significantly to its prolonged survival during mouse infections.²⁹ Studies have demonstrated that mig14 may confer resistance to polymyxin B in S. Typhimurium by decreasing outer membrane permeability and enhancing biofilm formation.²⁹ This finding implies that the emergence of polymyxin B resistance in CRSE would present a significant challenge in the clinical management of infections. This finding underscores the necessity for developing appropriate response strategies to address the emergence of highly toxic and resistant bacterial strains in the future.

Utilizing the NCBI Pathogen Detection Portal database, we conducted a phylogenetic analysis of the relationships among S. Typhimurium strains 21CR6302 and 23CR6032, along with 21 other CRSE isolates from humans worldwide; we observed that the serotypes, ST types, and presence of carbapenemase genes in CRSE strains differ across countries. A clone of multidrug-resistant S. Kentucky ST198 emerged in Egypt in 1989 and spread into Europe and Asia, causing the global spread of quinolone-resistant Salmonella.³⁰ CRSE S. Kentucky ST198 was prevalent in the United Kingdom in our study. Wu et al. also reported that the ST type of CRSE strain in the United Kingdom is mainly ST198.³¹ This study suggests that the emergence of CRSE S. Kentucky ST198, similar to the outbreak in Egypt, may lead to the global spread and prevalence of the CRSE strain. This is a huge potential danger to global public health. In recent years, S. Typhimurium ST34 has gradually replaced the “traditional” S. Typhimurium ST19, and S. Typhimurium ST34 has attracted global attention due to its rapid spread and resistance to multiple key antibiotics.³² A study in China shows that S. Typhimurium ST34 had high incidence in children and elderly, and exhibits multidrug resistance.³³ In our study, we found two CRSE S. Typhimurium ST34 from children in our hospital, and CRSE S. Typhimurium ST34 had also been found in other regions of China.^34–36 The number of cgSNPs differences among the strains in China indicates that they appear sporadically. These phenomena indicate that the emergence and spread of CRSE S. Typhimurium ST34 seriously endangers people’s health, especially children, who may face the dilemma of no cure. Notably, most CRSE strains in China are of the serovar Typhimurium, and these strains all carry the carbapenemase gene bla_NDM, which indicates that NDM-producing CRSE strains are likely to have been prevalent and disseminated in China. Ke et al. also reported the transmissibility of NDM-producing strains in China.³⁷ However, serovar Kentucky is endemic, and bla_OXA-48 is the main carbapenemase gene in the United Kingdom. Due to the limitations of the database and the lack of whole genome sequencing data for some strains, the strains from other regions have not been analyzed, such as KPC-2-Producing S. Salmonella in Argentina, USA, and Colombia, S. Waycross carrying bla_IPM-4 in Australia, S. Kentucky carrying bla_VIM-2 in Morocco, Salmonella enterica carrying bla_NDM-1 in India and Pakistan, and Salmonella carrying bla_OXA-48 in France and Switzerland, and so on.²⁰ These findings suggested significant variations in the serotypes of strains and the prevalence of carbapenemases across different regions. This was enough to draw human attention to the spread of drug resistance. Therefore, the global detection of carbapenem-resistant strains was of great significance to prevent the spread of resistant strains, the occurrence of infection events, and clinical treatment.

Conclusions

Our research provides the comprehensive analysis of the resistance spectrum, virulence, and global distribution of CRSE isolates from human cases. The study has shown that the ST type, resistance genes, and serotypes of CRSE isolates from human vary in different regions. These findings have significant implications for the clinical management of infections caused by CRSE and underscore the importance of global health initiatives aimed at mitigating the associated health risks. We advocate for enhanced real-time surveillance by international health organizations to prevent the further dissemination of CRSE.

Authors’ Contributions

Conceptualization: S.L. and M.Z. Data curation: S.L. Funding acquisition: M.Z. Investigation: J.X. and C.F. Methodology: S.L. Project administration: M.Z. Resources: M. Z. Software: Y.Z. Supervision: S.L. and M.Z. Validation: X.Z. Visualization: S.L. Writing—original draft: S.L. and X.Z. Writing—review and editing: S.L. and M.Z.

Footnotes

Acknowledgments

The authors sincerely appreciate the invaluable contributions and collaboration of all health care professionals from the Department of Clinical Laboratory, Children’s Hospital, Zhejiang University School of Medicine, who participated in this study.

Ethics Statement

The research involving human participants was reviewed and approved by the Research and Ethics Committee of Children’s Hospital, Zhejiang University School of Medicine (Approval NO. 2021-IRB-031). The Research and Ethics Committee has approved the complete study design. This study was conducted in full compliance with the ethical principles outlined in the Declaration of Helsinki. In accordance with both national regulations and institutional policies, written informed consent from participants’ legal guardians or next of kin was not required for participation in this research.

Data Availability Statement

The genome sequences of S. Typhimurium 21CR6302 and 23CR6032 strains were uploaded to GenBank with accession numbers JBIOZT000000000 and JBIOZU000000000. This database of the NCBI Pathogen Detection Portal is publicly available, and unrestricted reuse is permitted.

Disclosure Statement

No competing financial interests exist.

Funding Information

This work was supported by research grants from Zhejiang Provincial Natural Science Foundation of China (No. LTGC23H200006), the Key Program of The Independent Design Project of National Clinical Research Center for Child Health (No. I23J0006), the “Pioneer” and “Leading Goose” R&D Program of Zhejiang Province (2023C03028), the Planned Science and Technology Project of Traditional Chinese Medicine of Zhejiang Province of China (No. 2023ZL352).

Supplemental Material

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Supplementary Material

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