Yanbing Li1,2,3*†
Refath Farzana3*†- 1State Key Laboratory of Complex Severe and Rare Diseases, Department of Clinical Laboratory, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- 2Graduate School, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China
- 3Department of Biology, Ineos Oxford Institute for Antimicrobial Resistance, University of Oxford, Oxford, United Kingdom
Klebsiella pneumoniae has evolved from an opportunistic pathogen into a formidable global threat, with hypervirulent strains now causing severe infections in healthy individuals and carbapenem-resistant variants achieving mortality rates exceeding 42%. This transformation can be driven by mobile genetic elements including plasmids, integrative conjugative elements (ICE), insertion sequences (ISs), transposons, and integrons. Recent discoveries reveal that these elements employ sophisticated mechanisms: conjugative virulence plasmids dissemination across bacterial populations; ICEs-mediated virulence traits transfer; and hybrid genetic elements simultaneously confer virulence and antimicrobial resistance. Understanding these molecular mechanisms is critical for developing targeted diagnostics and therapeutics that disrupt mobile element mobility, offering promising strategies to combat the convergence of hypervirulence and resistance in this WHO priority pathogen.
Background: from opportunistic pathogen to superbug, the evolution of Klebsiella pneumoniae
Klebsiella pneumoniae represents a paradigmatic example of rapid pathogenic evolution in the modern clinical era. Historically recognised as an opportunistic pathogen primarily causing nosocomial infections in immunocompromised hosts, this Gram-negative bacterium has undergone a remarkable transformation that fundamentally challenges traditional concepts of bacterial pathogenicity (Paczosa and Mecsas, 2016). Classical K. pneumoniae (cKP) isolates retain this profile, exhibiting high genetic diversity and typically low virulence (Kochan et al., 2023). The pivotal recognition of this evolutionary shift of this organism occurred in 1986 when Liu et al. documented seven cases of invasive K. pneumoniae infections manifesting as hepatic abscess and septic endophthalmitis in previously healthy community-dwelling individuals without underlying biliary tract disease. This seminal observation marked the emergence of what would later be characterised as hypervirulent K. pneumoniae (hvKp), distinguished by its capacity to cause severe invasive diseases in immunocompetent hosts (Liu et al., 1986).
Subsequent decades witnessed parallel K. pneumoniae evolution along two increasingly convergent pathways. The first involves hypervirulence development, characterised by enhanced capsular polysaccharide (CPS) production (mucoid phenotype), iron acquisition systems (aerobactin, yersiniabactin, salmochelin), and systemic infection establishment from initial colonisation sites (Shon and Russo, 2012; Gu et al., 2018). The second pathway encompasses extensive antimicrobial resistance (AMR) acquisition, particularly emergence of carbapenem-resistant K. pneumoniae (CRKP) which has been linked to mortality rates as high as 42.86% (Chen et al., 2022). Trait convergence has culminated in carbapenem-resistant hypervirulent K. pneumoniae (CR-hvKp), a true “superbug” combining exceptional pathogenic potential with broad AMR profiles (Gu et al., 2018; Roulston et al., 2018). Complexity intensifies through highly clonal populations and persistence of environmental reservoir (hospital surfaces, water systems, medical equipment), facilitating rapid healthcare dissemination (Paczosa and Mecsas, 2016; Farzana et al., 2023).
Given substantial pathogenic potential, rising AMR challenges, and epidemiological significance as both harmless coloniser and pathogen, K. pneumoniae has garnered extensive scientific attention. In recognition of these concerns, the 2024 WHO Bacterial Priority Pathogens List (BPPL) formally designated carbapenem-resistant K. pneumoniae as the top “critical priority” pathogen, assigning it the highest possible risk score (84%) amongst 24 evaluated bacteria (Sati et al., 2025). This designation reflects its high burden of disease, increasing resistance trends, treatment difficulty, and significant public-health impact globally. Given its substantial pathogenic potential, evolving resistance profiles, and epidemiological relevance, K. pneumoniae remains a major threat and therefore continues to warrant focused research and surveillance.
Central to understanding this rapid pathogenic evolution is recognising that the transformative capacity of K. pneumoniae can be driven by mobile genetic elements (MGEs). These genetic structures including plasmids, integrative and conjugative elements (ICEs), insertion sequences (ISs), transposons, and integrons, function as horizontal gene transfer vehicles, enabling rapid virulence and resistance trait dissemination across diverse bacterial populations and accelerating bacterial adaptation to selective pressures (Ernst et al., 2020; Farzana et al., 2023).
Despite significant advances in understanding K. pneumoniae pathogenicity, critical knowledge gaps remain regarding precise mechanisms governing MGE-mediated virulence acquisition and dissemination. Regulatory networks controlling virulence gene expression, molecular bases of MGE mobility, and factors determining successful horizontal transfer events remain incompletely characterised (Haudiquet et al., 2021).
This review provides comprehensive overview of MGEs associated with K. pneumoniae virulence. We focus on mechanisms underlying pathogenic trait transfer between plasmids and chromosomes, and amongst different bacterial strains. By highlighting established and predicted virulence factors and analysing their genetic contexts, this review elucidates MGE roles in shaping K. pneumoniae pathogenic potential.
Data systematically collected from eligible studies included: virulence gene location (chromosome or plasmid); MGEs pertinent to virulence, including size and classification (e.g., group for insertion sequences; replicon type for plasmids); bacterial host harbouring virulence genes; sequence type (ST) and K-antigen (capsular type) of the host bacteria; as well as year, country and source of isolation of bacterial host.
Understanding hypervirulence: genetic determinants in Klebsiella pneumoniae
Since the discovery of hvKp, how to genetically and phenotypically classify hvKp has become an urgent question. Early investigations identified the mucoid phenotype and siderophore systems as key contributors to hvKp characteristics (Figure 1A) (Nassif and Sansonetti, 1986; Nassif et al., 1989). This review categorise the virulence genes in K. pneumoniae according to their mechanisms of action (Table 1).
Figure 1. Major virulence factors in K. pneumoniae. (A) Key virulence genes are distributed across the chromosome and virulence plasmids. Chromosomally encoded siderophores include ent and ybt, the latter often located on an ICE alongside the clb locus responsible for colibactin biosynthesis. Virulence plasmids encode siderophore systems such as iuc, iro, and regulatory genes like peg-344, all contributing to increased pathogenicity. Additional virulence factors, such as fimbriae, also contribute to K. pneumoniae virulence. (B) Regulatory factors of CPS in K. pneumoniae. Solid arrows denote promotion, and dashed arrows indicate repression. Positive regulators, including RmpA, KvrA, KvrB, and the RcsA/RcsBCD phosphorelay system, activate transcription of key capsule biosynthesis genes (galF, gnd, ugd, wza, wzx, wzb, and wzc), thereby enhancing CPS production and contributing to the hypermucoviscous phenotype. In contrast, CRP and nutrient- or stress-associated signals (N-HS) act as negative regulators that repress cps transcription. (C) The siderophore systems enterobactin (ent), yersiniabactin (ybt), salmochelin (iro), and aerobactin (iuc) are present. Each siderophore binds iron outside the bacterial cell and delivers it to specific outer-membrane receptors. These uptake pathways allow the bacterium to overcome host iron limitation and support its growth and virulence. TBDT: TonB-dependent transporter. The figure is created by BioRender.
Table 1. Summary of virulence genes in K. pneumoniae.
Essential genes for capsule and hypermucoviscosity production
CPS overproduction represents a critical virulence factor enabling immune evasion and facilitating survival within host environments. Capsule biosynthesis is encoded by the cps gene cluster, including genes for sugar synthesis (galF, gnd, ugd), polymerisation (wzy, wzx), and transport (wza, wzb, wzc) (Xu et al., 2024). Single-nucleotide polymorphisms (SNPs) in wzc (Ernst et al., 2020) and K1-specific wzy polymerase formerly known as magA (Fang et al., 2010) increase mortality in animal models. The cps locus is regulated by plasmid-borne and chromosomal factors: the hypermucoviscous phenotype associates with K1 and K2 serotypes through the rmp operon (rmpA-rmpC-rmpD) (Walker Kimberly et al., 2019; Walker Kimberly et al., 2020; Wacharotayankun et al., 1993) which are typically plasmid-encoded but also found in chromosome (Hsu et al., 2011). Chromosomal regulators (rcsA, rcsB, and the Rcs phosphorelay system) respond to stress and upregulate cps genes (Meng et al., 2021). Additional chromosomally encoded regulators like kvrA, kvrB, fur, and lon modulate capsule expression (Palacios et al., 2018), while cAMP receptor protein (CRP) negatively regulates by repressing cps transcription (Lin et al., 2013). Phospholipid transport systems such as Mla system, MlaA, Phospholipase D (PLD) maintain membrane integrity and capsule stability (Lin et al., 2013; Dorman et al., 2018) (Figure 1B). Key serotypes (K1, K2, K5, K20, K54, K57) co-associate with virulence genes (rmpA, rmpA2, iucA, iroB, peg-344, and wzy(K1)). K1 and K2 are most studied, with magA specific to K1 and rmpA/rmpA2 detected in nearly all K1 (99.4%) and K2 (98.6%) isolates, contributing to high lethality and serum resistance, respectively (Tian et al., 2025).
Iron acquisition systems
Iron, though essential for bacterial metabolism, is sequestered by host proteins. K. pneumoniae produces siderophores to scavenge iron, crucial for infection survival (Schalk, 2025). All strains possess the chromosomal enterobactin (Ent) system with receptor fepA (Baghal et al., 2010). The chromosomal yersiniabactin (Ybt) system contributes to pathogenicity. Plasmid-borne aerobactin (iucABCD-iutA) and salmochelin (iroBCDN) systems strongly associate with hvKp (Holt et al., 2015). Amongst iro genes, iroN and iroB support efficient iron uptake (Müller et al., 2009), while kfu and tonB promote fitness and virulence (Hsieh et al., 2008) (Figure 1C). In hvKp, the siderophore biosynthesis gene entC is regulated by Ferric-uptake regulator (Fur) and RcsAB complex. Fur repression is relieved and RcsAB activates entC transcription under iron limitation, enhancing siderophore production and virulence (Yuan et al., 2020).
Genotoxin
An important virulence factor in K. pneumoniae is colibactin, a genotoxin first identified in Escherichia coli (Choby et al., 2020). Colibactin induces DNA damage, causing cell cycle arrest, senescence, or apoptosis, impairing infection resolution (Faïs et al., 2018). It disrupts epithelial barriers, facilitates tissue translocation, and modulates immunity by reducing pro-inflammatory signals (Lu et al., 2017). Synthesised by nonribosomal peptide synthetases encoded in the pks locus, typically within a chromosomal ICE. ICE facilitates horizontal transfer of colibactin-associated virulence.
Other virulence genes
Experimentally validated genes include peg-344, mrk fimbriae, moaR and kva15 regulators, kvgAS signalling, and allantoin metabolism (Lai et al., 2003; Chou et al., 2004; Tu et al., 2009; Bulger et al., 2017). ArcZ, a small RNA regulator, represses virulence genes (Wu et al., 2024). CRISPRi screening identified cell envelope genes (tolB, tolR, pal, lpp, ompA, waaL, nlpI) contributing to virulence through maintaining membrane stability (Zhu et al., 2023).
Plasmid-mediated dissemination of hypervirulence in Klebsiella pneumoniae
The clinical significance of virulence plasmids was first recognised when Nassif et al. identified a 180 kb plasmid encoding aerobactin and the mucoid phenotype, correlating with virulence phenotypes in K1 and K2 isolates (Nassif and Sansonetti, 1986). Subsequent epidemiological studies demonstrated global dissemination (Struve et al., 2015; Lei et al., 2024). Struve et al. showed that all 30 K1/K2 hvKp strains from patients with liver abscess or community-acquired pneumonia across seven countries (Africa, Asia, Europe, North America) during 1996–2012 harboured pLVPK-like plasmids, though some contained gene deletions (Struve et al., 2015). Additional virulence plasmids underscore their global spread and evolutionary significance. For example, pVir_030666 in Klebsiella variicola encodes multiple virulence determinants including mucoid phenotype regulators (rmpA, rmpA2), aerobactin (iucABCD-iutA), salmochelin (iroBCDN), and yersiniabactin (irp1-2, ybtAEPQSTUX), exhibiting enhanced virulence in larval infection models (Lu et al., 2018).
Most plasmid-mediated virulence in K. pneumoniae is largely driven by this conserved set of genes that enhance capsule formation, iron acquisition, and metabolic fitness. As discussed in the previous part, rmpA and rmpA2 play central roles in increasing transcription of the cps locus, leading to the hypermucoviscous phenotype (Hu et al., 2023). This thick capsule protects the bacterium from complement-mediated killing and phagocytosis, enabling invasive disease even in healthy hosts.
In parallel, plasmid-encoded siderophore systems such as aerobactin (iucABCD-iutA) and salmochelin (iroBCDN) provide high-affinity mechanisms for iron uptake, allowing the pathogen to overcome host nutritional immunity and sustain rapid growth during infection (Hong et al., 2024).
Additional loci, including peg-344 and plasmid-associated variants of the yersiniabactin cluster, further enhance fitness and facilitate tissue invasion. Together, these virulence determinants act synergistically to promote virulence plasmid dissemination, persistence, and severe clinical manifestations.
Classical non-conjugative virulence plasmids
Classical virulence plasmids have been systematically classified by genetic architecture and virulence gene content. The two predominant types are KpVP-1, characterised by iuc1, iro1, rmpA, and rmpA2, and KpVP-2, carrying iuc2, iro2, and rmpA (Struve et al., 2015). pK2044 (224,152 bp), originally identified in a K1 hvKp strain, is the prototypical representative of the KpVP-1 lineage, whereas pLVPK (219,385 bp), first described in a K2 strain, is the representative plasmid of the KpVP-2 group. These large plasmids harbour key virulence determinants including aerobactin synthesis genes (iuc), metabolite transporter peg-344, and mucoid phenotype regulators rmpA and rmpA2. Loss of these plasmids significantly attenuates virulence in animal models (García-Cobos et al., 2025). Genomic surveillance revealed considerable diversity beyond classical archetypes. Novel variants include plasmids carrying iuc3, iuc5 (with or without iro5), and novel iuc/iro allelic variants, demonstrating ongoing evolution and horizontal transfer across K. pneumoniae populations. Divergent virulence plasmids like pKP35_vir and pKP36_vir, sharing limited sequence homology (<40% coverage) with KpVP-1 and KpVP-2, have been designated KpVP-3, expanding recognised diversity (Struve et al., 2015).
Conjugative virulence plasmids
A critical evolutionary development is the emergence of conjugative virulence plasmids, combining self-transmissibility with virulence gene cargo, enabling horizontal dissemination across bacterial populations. The first characterised conjugative virulence plasmid, p15WZ-82_Vir, was identified in K. variicola and formed through integration of a 100-kb virulence region into a conjugative IncFIB backbone. This chimeric plasmid retained key virulence loci including rmpA, truncated rmpA2 (rmpA2Δ), aerobactin operon (iucABCD-iutA), and salmochelin cluster (iroBCDN). Experimental conjugation assays demonstrated successful transfer to multiple Klebsiella species, with transconjugants exhibiting significantly enhanced virulence, confirming both mobility and functional virulence contribution (Yang et al., 2019). Table 2 summarises ten individual conjugative virulence plasmids reported in previous studies. These plasmids were described as specific, well-characterised examples of plasmid-mediated hypervirulence (Table 2; Figure 2).
Table 2. Summary of conjugative virulence plasmid in K. pneumoniae.
Figure 2. Comparative genomic alignment of representative conjugative virulence plasmids in K. pneumoniae. Linear comparison of virulence plasmids from K. pneumoniae reveals extensive sequence homology and structural rearrangements. Blue shaded areas represent shared regions with ≥99% nucleotide identity, with colour intensity reflecting sequence similarity. Arrows indicate predicted coding sequences, with virulence-associated genes (e.g., iuc, iro, rmpA, rmpA2, peg-344) highlighted in red. The figure is created by EasyFig (2.2.5).
Emerging conjugative variants
Most virulence plasmids in K. pneumoniae are nonconjugative, lacking essential plasmid-transfer genes. However, compelling evidence exists for horizontal transfer between plasmids and chromosomes through various mechanisms (Nguyen et al., 2024). Structural complexity is exemplified by pLVPK, containing 13 ISs, likely representing sequential acquisition of horizontally transferred genes (Chen et al., 2004). Huang et al. described a unique virulence plasmid carrying ybt4, the only reported plasmid-encoded yersiniabactin locus (Huang et al., 2023). This 165-kb IncFIBκ/FIIκ plasmid contains a tra-trb conjugation region, and in pKP35_vir, the ybt4 locus is flanked by mobile elements IS1 and Tn2, suggesting spread via genetic recombination (Huang et al., 2023). The molecular mechanisms governing virulence plasmid conjugation and stability remain incompletely characterised (Shon and Russo, 2012), necessitating comprehensive genomic characterisation of plasmid architecture, including core virulence gene cassettes and MGEs, to understand pathogenesis and develop surveillance frameworks (Ahmed et al., 2021).
ICEs as drivers of Klebsiella pneumoniae virulence dissemination
ICEs are MGEs that integrate into bacterial chromosomes and transfer themselves through conjugation. ICEs consist of cargo modules and functional conjugation systems. Cargo genes, unrelated to their maintenance, provide selective advantages such as antimicrobial resistance genes (ARGs), heavy metal tolerance, or enhanced metabolic capabilities (Johnson and Grossman, 2015). Several ICEs carry virulence-associated cargo genes, contributing to pathogenicity. For instance, P. aeruginosa pathogenicity island 1 (PAPI-1) is a functional ICE that mediate horizontal transfer of virulence traits and may enhance ecological fitness, allowing colonisation and adaptation to specific hosts or environments (Carter et al., 2010).
The widespread distribution of ICEs across bacterial populations has been revealed through large-scale genomic analysis, which identified over 300 putative ICEs across more than 1,000 bacterial genomes. ICEs are found in both pathogenic and non-pathogenic bacteria, with a broader distribution than conjugative plasmids (Guglielmini et al., 2011). ICEs typically integrate at tRNA loci, with one study reporting 73% of strains harboured ICE insertions at one or more of four asparagine tRNA genes (Marcoleta et al., 2016).
They were first characterised in Enterococcus faecalis during the late 1980s, revealing tetracycline resistance transfer without plasmids (Franke and Clewell, 1981). The ICE in K. pneumoniae (ICEKp), extensively characterised by Lin et al., is defined by biosynthetic genes for siderophore yersiniabactin (Lin et al., 2008). ICEKp1 spans approximately 76 kilobases and was identified in hvKp strain NTUH-K2044. ICEKp1 demonstrated substantially higher prevalence in hvKp (38/42) compared to cKp strains (5/32) (Lin et al., 2008). ICEKp1 was also detected in in several members of the K. pneumoniae species complex (Breurec et al., 2016). Recent studies show ICEs are particularly prevalent in K. pneumoniae but occasionally acquired by other Enterobacteriaceae (Putze et al., 2009; Paauw et al., 2010). In a large-scale genomic survey of 2,498 K. pneumoniae isolates, approximately 40% of ICEKp carried ybt, and around 14% carried clb (Lin et al., 2008).
ICEKp elements are characterised by a conserved backbone including P4-like integrase (int), the 29-kb ybt locus, and a ~ 14-kb mobilisation module encoding xis, virB-type IV secretion system (T4SS), oriT, and mobBC (Lin et al., 2008; Marcoleta et al., 2016). Fourteen distinct structural variants, designated ICEKp1 through ICEKp14, have been identified, each associated with specific lineages of yersiniabactin and colibactin loci (Table 3) (Lam et al., 2018). Distinct cargo gene clusters at the right end allow classification into these structural variants.
Table 3. Comparative features of ICEKp variants in K. pneumoniae.
Most ICEKp variants are associated with a single ybt lineage, suggesting co-evolution, while ICEKp10, harbouring the clb (colibactin) locus, is linked to multiple ybt lineages, indicating repeated acquisition events. The presence of clb has been strongly associated with enhanced pathogenicity in both hvKp and cKp backgrounds, particularly in severe invasive infections. In contrast to ICEKp1, which primarily harbours ybt, iro, and rmpA, ICEKp10 lacks these additional virulence genes but contributes to hypervirulence through colibactin-mediated genotoxicity. Phylogenetic analysis of clb sequences revealed three distinct lineages (clb1, clb2A, clb2B), each associated with a specific ybt lineage, suggesting independent acquisitions into ICEKp. Certain ICEKp variants lacking typical mobilisation machinery indicate evolutionary divergence or specialisation within specific lineages (Table 3) (Lam et al., 2018).
ICEs spread virulence or resistance traits by excising from the chromosome, forming a circular intermediate, and transferring single-stranded DNA to recipient cells through a T4SS (Lee et al., 2010). Similar to other ICEs, ICEKp integrates into the chromosome at a conserved tRNA-associated attachment site (attB) through an ICE-encoded integrase, usually a tyrosine recombinase (Guérillot et al., 2014). After transfer, the ICE is re-integrated into the recipient chromosome, allowing stable maintenance of the virulence locus. The capability of ICEKp to mobilise virulence-associated loci, including ybt and clb, along with metabolic modules facilitating bacterial nutrient uptake, indicates its critical role in shaping pathogenic potential across various clonal backgrounds.
How do tiny DNA segments control bacterial virulence?
ISs are the simplest form of mobile elements, typically consisting of a transposase gene flanked by short, inverted repeats. Though small, they have significant functional impacts by disrupting genes, modifying promoter activity, or facilitating genomic rearrangements (Wei et al., 2025). In K. pneumoniae, IS element involvement in virulence has been demonstrated in recent years, particularly through disruption of capsule biosynthesis gene wcaJ (Wang et al., 2022). Hypervirulent isolates of ST23-K1 strain harbour IS elements, such as ISKpn26 or ISKpn74, which insert within wcaJ and induce frameshift mutations. This insertion significantly diminishes CPS production (Wang et al., 2022). Furthermore, IS5/ISKox3 elements have been observed associated with key capsule synthesis genes (wcaJ, wza, wzc) in hvKp. This association leads to non-mucoid phenotypes in vitro. Importantly, excision of these IS elements restores capsule production in vivo, thereby recovering hypervirulence capacity (Wei et al., 2025). The specific IS elements associated with K. pneumoniae virulence are detailed in Table 4.
Table 4. Summary of insertion sequence in K. pneumoniae.
IS-mediated inactivation of capsule biosynthesis genes conferred lower fitness cost and enhanced conjugation frequency of a blaKPC-2 resistance plasmid (Wang et al., 2022). These findings highlight a dynamic IS-mediated “capsule ON–OFF–ON” mechanism that not only alters virulence but also promotes horizontal transfer of multidrug resistance in hvKp (Wei et al., 2025). For instance, ISKpn74 has been identified as a significant factor altering virulence through two distinct yet contrasting mechanisms. Typically, plasmid-associated, ISKpn74 is integrated upstream of rmpA and rmpA2, enhancing expression of virulence traits such as hypermucoviscosity and increased siderophore production (Huang et al., 2024). Conversely, another study identified ISKpn74 within the chromosomal framework of an ST20 isolate, where its insertion occurs between K and O antigen loci, suggesting potential disruption of capsule biosynthesis pathways (Eger et al., 2021).
Beyond influencing strain virulence, ISs significantly contribute to structural evolution of virulence elements by facilitating transfer between plasmids and chromosomes. Research shows IS elements like ISKpn28 and IS26 are instrumental in forming large fusion plasmids, arising from recombination events between classical virulence plasmids (such as pK2044-like) and resistance plasmids (like pNDM-Mar-like) (Wang S. et al., 2024). These hybrid plasmids contain key virulence genes, including rmpA2 and the iucABCD-iutA operon. Furthermore, IS-mediated integration of these genetic fragments into the chromosome has been documented (Tian et al., 2022; Wang S. et al., 2024).
Additional mobile elements: transposons and integrons
Transposons mobilise large genetic regions, including virulence cassettes, facilitating horizontal transfer across strains. The rapid evolution of CR-hvKp stems from transposon-mediated co-selection and co-transfer of virulence and resistance determinants (Gray et al., 2024). Tn3 family members frequently mobilise virulence genes in K. pneumoniae (Tian et al., 2023). A conserved ~16.2 kb composite transposon on IncFIB/FII plasmids carries the iuc3 aerobactin operon, enabling dissemination across animal and human reservoirs (Kaspersen et al., 2023). Tn7074-like transposons integrate complete virulence cassettes (rmpA2, iucABCD-iutA, peg-344) into conjugative plasmids, significantly enhancing recipient strain virulence (Li et al., 2025).
Integrons capture, assemble, and express gene cassettes encoding virulence factors (Chen et al., 2018). Integrons lack self-mobility and rely on ISs, transposons, or plasmids for dissemination (Farajzadeh Sheikh et al., 2024). Integrons, particularly class 1 integrons, are capable of shaping K. pneumoniae virulence potential (Chen et al., 2018). Studies found 74% of clinical isolates harboured class 1 integrons, with higher wcaG capsule gene prevalence (Derakhshan et al., 2016). Another study revealed 19.1% of integrons co-localised with virulence loci, including iucABCD-iutA, rmpA2, and peg-344 (Li et al., 2025).
MGEs-driven convergence of hypervirulence and resistance
CR-hvKP strains exhibit both hypervirulence and high-level AMR, spreading globally and presenting significant clinical threats (Karampatakis et al., 2023; Chen et al., 2020; Ahmed et al., 2021; Chen et al., 2021). An ST11 K. pneumoniae strain gained virulence after acquiring pLVPK-like plasmid pVir-CR-hvKP4, despite a 41,231-bp deletion including rmpA and iro loci (Gu et al., 2018). Salmochelin (iro) appears non-essential for systemic infection (Russo et al., 2015), and rmpA/rmpA2 redundancy maintains pathogenicity (Cheng et al., 2010; Russo et al., 2015). Aerobactin production was predicted to be essential for hypervirulence (Russo et al., 2014).
There is evidence of harbouring hybrid plasmid pVir (297,984 bp), combining sequences from virulence plasmids pK2044/pLVPK and resistance plasmid pPMK-NDM in ST11 strain from Taiwan (Fang et al., 2025). Despite harbouring iroBCDN, iucABCD-iutA, rmpA, and rmpA2, it showed limited virulence in mouse models, suggesting unidentified virulence factors exist in the truncated regions from pK2044/pLVPK.
Tn3-family transposons mediate fusion between virulence and resistance plasmids, creating self-transmissible hybrids encoding both determinants (Ramirez et al., 2014; Nicolas et al., 2015; Tian et al., 2023). Integrons within multidrug-resistant IncFII plasmids, flanked by IS26, facilitate simultaneous horizontal transmission of resistance and virulence genes (Li et al., 2025).
Concluding remarks and future directions
K. pneumoniae exemplifies a high-risk pathogen combining AMR and hypervirulence through MGEs acquisition, threatening both immunocompromised and healthy populations globally (García-Cobos et al., 2025). Despite extensive research on resistance mechanisms, critical knowledge gaps persist in the current understanding of this organism: studies remain confined to limited clonal groups and serotypes (Wyres et al., 2019); the hypervirulence-resistance relationship is underexplored (García-Cobos et al., 2025); virulence gene functions require deeper characterisation (Derakhshan et al., 2016); and MGEs-mediated mobility mechanisms remain incompletely understood (Haudiquet et al., 2021).
While over 200 published reviews have examined K. pneumoniae virulence since 1977, few address how virulence traits are acquired, mobilised, and maintained molecularly (Russo and Marr, 2019; Yang et al., 2021). Critically, plasmid-chromosome exchanges and smaller mobile elements (ISKpn74, Tn3 transposons) facilitating gene dissemination have received insufficient scientific attention (Haudiquet et al., 2021).
Understanding MGEs-mediated virulence dissemination is essential for advancing surveillance and therapeutics. Characterisation of MGE-mediated virulence gene mobility, including the roles of integrases, transposases, insertion sequences, and recombination hotspots, can enhance molecular diagnostic platforms by enabling the detection of both established virulence markers (such as rmpA, iucABCD, and clb) and their associated genetic mobility signatures (Farajzadeh Sheikh et al., 2024). Such integrated surveillance approaches would improve the identification of high-risk hypervirulent strains with enhanced horizontal transfer potential, thereby informing more effective infection control measures by distinguishing between clonal dissemination and independent MGE-mediated acquisition events across diverse lineages (Farajzadeh Sheikh et al., 2024). Furthermore, elucidating the molecular mechanisms governing ICE excision, plasmid conjugation, and IS-mediated genomic rearrangements may reveal novel therapeutic targets, including MGE-encoded integrases, relaxases, and T4SS components, whose inhibition could disrupt the horizontal spread of hypervirulence and AMR determinants (Wang Q. et al., 2024). Given the convergence of hypervirulence and carbapenem resistance traits mediated by hybrid plasmids and composite transposons, targeted disruption of MGE mobility machinery represents a promising strategy to limit the emergence and dissemination of CR-hvKp strains, which pose formidable challenges to global public health.
Author contributions
YL: Investigation, Data curation, Writing – review & editing, Formal analysis, Writing – original draft. RF: Writing – review & editing, Supervision, Writing – original draft, Investigation, Funding acquisition.
Funding
The author(s) declared that financial support was received for this work and/or its publication. YL is the recipient of fellowship funding by the China Scholarship Council. RF is funded by Ineos Oxford Institute for Antimicrobial Research. Publication fees were provided by Ineos Oxford Institute for Antimicrobial Research.
Conflict of interest
The author(s) declared that this work was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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Supplementary material
The Supplementary material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fmicb.2025.1730961/full#supplementary-material
SUPPLEMENTARY FIGURE 1 | Mechanism of ICE excision, transfer, and integration between bacteria. ICEs are found integrated in the donor chromosome at a specific attachment site (attB). Upon activation, ICEs excise via an integrase and recombination directionality factor (RDF/xis), forming a circular DNA intermediate. A relaxase introduces a nick at the origin of transfer (oriT) and facilitates the transfer of single-stranded DNA through a type IV secretion system (T4SS) into the recipient cell. Following transfer, the ICE is recircularised, undergoes second-strand synthesis, and is integrated into the recipient chromosome at an attB site by the integrase, completing the horizontal transfer process. The figure is created by BioRender.
References
Ahmed, M., Yang, Y., Yang, Y., Yan, B., Chen, G., Hassan, R. M., et al. (2021). Emergence of hypervirulent carbapenem-resistant Klebsiella pneumoniae coharboring a Bla(NDM-1)-carrying virulent plasmid and a Bla(KPC-2)-carrying plasmid in an Egyptian hospital. mSphere 6:e00088-21. doi: 10.1128/mSphere.00088-21,
Baghal, S. M. L., Gargari, S. L. M., and Rasooli, I. (2010). Production and immunogenicity of recombinant ferric enterobactin protein (FepA). Int. J. Infect. Dis. 14, e166–e170. doi: 10.1016/j.ijid.2009.12.009,
Breurec, S., Melot, B., Hoen, B., Passet, V., Schepers, K., Bastian, S., et al. (2016). Liver abscess caused by infection with community-acquired Klebsiella quasipneumoniae subsp. quasipneumoniae. Emerg. Infect. Dis. 22:529. doi: 10.3201/eid2203.151466,
Bulger, J., MacDonald, U., Olson, R., Beanan, J., and Russo, T. A. (2017). Metabolite transporter PEG344 is required for full virulence of hypervirulent Klebsiella pneumoniae strain hvKP1 after pulmonary but not subcutaneous challenge. Infect. Immun. 85. doi: 10.1128/iai.00093-17,
Carter, M. Q., Chen, J., and Lory, S. (2010). The Pseudomonas aeruginosa pathogenicity island PAPI-1 is transferred via a novel type IV pilus. J. Bacteriol. 192, 3249–3258. doi: 10.1128/jb.00041-10,
Chen, Y. T., Chang, H. Y., Lai, Y. C., Pan, C. C., Tsai, S. F., and Peng, H. L. (2004). Sequencing and analysis of the large virulence plasmid pLVPK of Klebsiella pneumoniae CG43. Gene 337, 189–198. doi: 10.1016/j.gene.2004.05.008,
Chen, D.-Q., Jiang, Y.-T., Feng, D.-H., Wen, S.-X., Su, D.-H., and Yang, L. (2018). Integron mediated bacterial resistance and virulence on clinical pathogens. Microb. Pathog. 114, 453–457. doi: 10.1016/j.micpath.2017.12.029
Chen, J., Ma, H., Huang, X., Cui, Y., Peng, W., Zhu, F., et al. (2022). Risk factors and mortality of carbapenem-resistant Klebsiella pneumoniae bloodstream infection in a tertiary-care hospital in China: an eight-year retrospective study. Antimicrob. Resist. Infect. Control 11:161. doi: 10.1186/s13756-022-01204-w,
Chen, Y., Marimuthu, K., Teo, J., Venkatachalam, I., Cherng, B. P. Z., De Wang, L., et al. (2020). Acquisition of plasmid with carbapenem-resistance gene Bla(KPC2) in hypervirulent Klebsiella pneumoniae, Singapore. Emerg. Infect. Dis. 26, 549–559. doi: 10.3201/eid2603.191230,
Chen, J., Zeng, Y., Zhang, R., and Cai, J. (2021). In vivo emergence of colistin and tigecycline resistance in carbapenem-resistant hypervirulent Klebsiella pneumoniae during antibiotics treatment. Front. Microbiol. 12:702956. doi: 10.3389/fmicb.2021.702956,
Cheng, H. Y., Chen, Y. S., Wu, C. Y., Chang, H. Y., Lai, Y. C., and Peng, H. L. (2010). RmpA regulation of capsular polysaccharide biosynthesis in Klebsiella pneumoniae CG43. J. Bacteriol. 192, 3144–3158. doi: 10.1128/jb.00031-10,
Choby, J. E., Howard-Anderson, J., and Weiss, D. S. (2020). Hypervirulent Klebsiella pneumoniae - clinical and molecular perspectives. J. Intern. Med. 287, 283–300. doi: 10.1111/joim.13007,
Chou, H. C., Lee, C. Z., Ma, L. C., Fang, C. T., Chang, S. C., and Wang, J. T. (2004). Isolation of a chromosomal region of Klebsiella pneumoniae associated with allantoin metabolism and liver infection. Infect. Immun. 72, 3783–3792. doi: 10.1128/iai.72.7.3783-3792.2004,
Derakhshan, S., Peerayeh, S. N., and Bakhshi, B. (2016). Association between presence of virulence genes and antibiotic resistance in clinical Klebsiella Pneumoniae isolates. Lab. Med. 47, 306–311. doi: 10.1093/labmed/lmw030,
Dorman, M. J., Feltwell, T., Goulding, D. A., Parkhill, J., and Short, F. L. (2018). The capsule regulatory network of Klebsiella pneumoniae defined by density-TraDISort. MBio 9:e01863-18. doi: 10.1128/mBio.01863-18,
Eger, E., Heiden, S. E., Becker, K., Rau, A., Geisenhainer, K., Idelevich, E. A., et al. (2021). Hypervirulent Klebsiella pneumoniae sequence type 420 with a chromosomally inserted virulence plasmid. Int. J. Mol. Sci. 22:9196. doi: 10.3390/ijms22179196,
Ernst, C. M., Braxton, J. R., Rodriguez-Osorio, C. A., Zagieboylo, A. P., Li, L., Pironti, A., et al. (2020). Adaptive evolution of virulence and persistence in carbapenem-resistant Klebsiella pneumoniae. Nat. Med. 26, 705–711. doi: 10.1038/s41591-020-0825-4,
Faïs, T., Delmas, J., Barnich, N., Bonnet, R., and Dalmasso, G. (2018). Colibactin: more than a new bacterial toxin. Toxins (Basel) 10:151. doi: 10.3390/toxins10040151,
Fang, C. T., Lai, S. Y., Yi, W. C., Hsueh, P. R., and Liu, K. L. (2010). The function of wzy_K1 (magA), the serotype K1 polymerase gene in Klebsiella pneumoniae cps gene cluster. J. Infect. Dis. 201, 1268–1269. doi: 10.1086/652183,
Fang, Y., Li, X., Wu, Z., Fang, Y., Wang, Y., Li, X., et al. (2025). Emergence of an XDR Klebsiella pneumoniae ST5491 strain co-harboring NDM-5, MCR-1.1, tmexCD1-toprJ1, and a novel plasmid carrying CTX-M-15. Front. Microbiol. 16:1581851. doi: 10.3389/fmicb.2025.1581851,
Farajzadeh Sheikh, A., Abdi, M., and Farshadzadeh, Z. (2024). Molecular detection of class 1, 2, and 3 integrons in hypervirulent and classic Klebsiella pneumoniae isolates: a cross-sectional study. Health Sci. Rep. 7:e1962. doi: 10.1002/hsr2.1962,
Farzana, R., Jones, L. S., Rahman, M. A., Sands, K., van Tonder, A. J., Portal, E., et al. (2023). Genomic insights into the mechanism of carbapenem resistance dissemination in Enterobacterales from a tertiary public heath setting in South Asia. Clin. Infect. Dis. 76, 119–133. doi: 10.1093/cid/ciac287,
Franke, A. E., and Clewell, D. B. (1981). Evidence for a chromosome-borne resistance transposon (Tn916) in Streptococcus faecalis that is capable of "conjugal" transfer in the absence of a conjugative plasmid. J. Bacteriol. 145, 494–502. doi: 10.1128/jb.145.1.494-502.1981,
García-Cobos, S., Oteo-Iglesias, J., and Pérez-Vázquez, M. (2025). Hypervirulent Klebsiella pneumoniae: epidemiology outside Asian countries, antibiotic resistance association, methods of detection and clinical management. Enferm. Infecc. Microbiol. Clin. (Engl. Ed.) 43, 102–109. doi: 10.1016/j.eimce.2024.12.008,
Gray, J., Torres, V. V. L., Goodall, E., McKeand, S. A., Scales, D., Collins, C., et al. (2024). Transposon mutagenesis screen in Klebsiella pneumoniae identifies genetic determinants required for growth in human urine and serum. eLife 12:RP88971. doi: 10.7554/eLife.88971,
Gu, D., Dong, N., Zheng, Z., Lin, D., Huang, M., Wang, L., et al. (2018). A fatal outbreak of ST11 carbapenem-resistant hypervirulent Klebsiella pneumoniae in a Chinese hospital: a molecular epidemiological study. Lancet Infect. Dis. 18, 37–46. doi: 10.1016/S1473-3099(17)30489-9,
Guérillot, R., Siguier, P., Gourbeyre, E., Chandler, M., and Glaser, P. (2014). The diversity of prokaryotic DDE transposases of the mutator superfamily, insertion specificity, and association with conjugation machineries. Genome Biol. Evol. 6, 260–272. doi: 10.1093/gbe/evu010,
Guglielmini, J., Quintais, L., Garcillán-Barcia, M. P., de la Cruz, F., and Rocha, E. P. (2011). The repertoire of ICE in prokaryotes underscores the unity, diversity, and ubiquity of conjugation. PLoS Genet. 7:e1002222. doi: 10.1371/journal.pgen.1002222,
Haudiquet, M., Buffet, A., Rendueles, O., and Rocha, E. P. C. (2021). Interplay between the cell envelope and mobile genetic elements shapes gene flow in populations of the nosocomial pathogen Klebsiella pneumoniae. PLoS Biol. 19:e3001276. doi: 10.1371/journal.pbio.3001276,
Holt, K. E., Wertheim, H., Zadoks, R. N., Baker, S., Whitehouse, C. A., Dance, D., et al. (2015). Genomic analysis of diversity, population structure, virulence, and antimicrobial resistance in Klebsiella pneumoniae, an urgent threat to public health. Proc. Natl. Acad. Sci. USA 112, E3574–E3581. doi: 10.1073/pnas.1501049112,
Hong, H. X., Huo, B. H., Xiang, T. X., Wei, D. D., Huang, Q. S., Liu, P., et al. (2024). Virulence plasmid with IroBCDN deletion promoted cross-regional transmission of ST11-KL64 carbapenem-resistant hypervirulent Klebsiella pneumoniae in Central China. BMC Microbiol. 24:400. doi: 10.1186/s12866-024-03564-2,
Hsieh, P. F., Lin, T. L., Lee, C. Z., Tsai, S. F., and Wang, J. T. (2008). Serum-induced iron-acquisition systems and TonB contribute to virulence in Klebsiella pneumoniae causing primary pyogenic liver abscess. J. Infect. Dis. 197, 1717–1727. doi: 10.1086/588383,
Hsu, C. R., Lin, T. L., Chen, Y. C., Chou, H. C., and Wang, J. T. (2011). The role of Klebsiella pneumoniae rmpA in capsular polysaccharide synthesis and virulence revisited. Microbiology (Reading) 157, 3446–3457. doi: 10.1099/mic.0.050336-0,
Hu, D., Chen, W., Wu, J., Luo, X., Yu, L., Qu, Y., et al. (2023). Coexistence of c-rmpA with p-rmpA and p-rmpA2 rather than excessive siderophores confers higher virulence in K1 Klebsiella pneumoniae. Pathology 55, 1004–1012. doi: 10.1016/j.pathol.2023.07.007,
Huang, L., Li, Y., Xu, C., Zhou, M., Wang, T., Wang, T., et al. (2023). A novel virulence plasmid encoding yersiniabactin, salmochelin, and RmpADC from hypervirulent Klebsiella pneumoniae of distinct genetic backgrounds. Antimicrob. Agents Chemother. 67:e0093523. doi: 10.1128/aac.00935-23,
Huang, J., Zhuang, J., Wan, L., Liu, Y., Du, Y., Zhou, L., et al. (2024). Genomic analysis and virulence assessment of hypervirulent Klebsiella pneumoniae K16-ST660 in severe cervical necrotizing fasciitis. Int. J. Med. Microbiol. 317:151635. doi: 10.1016/j.ijmm.2024.151635,
Johnson, C. M., and Grossman, A. D. (2015). Integrative and conjugative elements (ICEs): what they do and how they work. Annu. Rev. Genet. 49, 577–601. doi: 10.1146/annurev-genet-112414-055018,
Karampatakis, T., Tsergouli, K., and Behzadi, P. (2023). Carbapenem-Resistant Klebsiella pneumoniae: Virulence Factors, Molecular Epidemiology and Latest Updates in Treatment Options. Antibiotics (Basel, Switzerland) 12:234. doi: 10.3390/antibiotics12020234
Kaspersen, H., Franklin-Alming, F. V., Hetland, M. A. K., Bernhoff, E., Lohr, I. H., Jiwakanon, J., et al. (2023). Highly conserved composite transposon harbouring aerobactin iuc3 in Klebsiella pneumoniae from pigs. Microb. Genom. 9:mgen000960. doi: 10.1099/mgen.0.000960,
Kochan, T. J., Nozick, S. H., Valdes, A., Mitra, S. D., Cheung, B. H., Lebrun-Corbin, M., et al. (2023). Klebsiella pneumoniae clinical isolates with features of both multidrug-resistance and hypervirulence have unexpectedly low virulence. Nat. Commun. 14:7962. doi: 10.1038/s41467-023-43802-1,
Lai, Y. C., Lin, G. T., Yang, S. L., Chang, H. Y., and Peng, H. L. (2003). Identification and characterization of KvgAS, a two-component system in Klebsiella pneumoniae CG43. FEMS Microbiol. Lett. 218, 121–126. doi: 10.1111/j.1574-6968.2003.tb11507.x,
Lam, M. M. C., Wick, R. R., Wyres, K. L., Gorrie, C. L., Judd, L. M., Jenney, A. W. J., et al. (2018). Genetic diversity, mobilisation and spread of the yersiniabactin-encoding mobile element ICEKp in Klebsiella pneumoniae populations. Microb. Genom. 4:e000196. doi: 10.1099/mgen.0.000196,
Lee, C. A., Babic, A., and Grossman, A. D. (2010). Autonomous plasmid-like replication of a conjugative transposon. Mol. Microbiol. 75, 268–279. doi: 10.1111/j.1365-2958.2009.06985.x,
Lei, T. Y., Liao, B. B., Yang, L. R., Wang, Y., and Chen, X. B. (2024). Hypervirulent and carbapenem-resistant Klebsiella pneumoniae: a global public health threat. Microbiol. Res. 288:127839. doi: 10.1016/j.micres.2024.127839,
Li, X., Chen, S., Lu, Y., Shen, W., Wang, W., Gao, J., et al. (2025). Molecular epidemiology and genetic dynamics of carbapenem-resistant hypervirulent Klebsiella pneumoniae in China. Front. Cell. Infect. Microbiol. 15:1529929. doi: 10.3389/fcimb.2025.1529929,
Lin, C. T., Chen, Y. C., Jinn, T. R., Wu, C. C., Hong, Y. M., and Wu, W. H. (2013). Role of the cAMP-dependent carbon catabolite repression in capsular polysaccharide biosynthesis in Klebsiella pneumoniae. PLoS One 8:e54430. doi: 10.1371/journal.pone.0054430,
Lin, T. L., Lee, C. Z., Hsieh, P. F., Tsai, S. F., and Wang, J. T. (2008). Characterization of integrative and conjugative element ICEKp1-associated genomic heterogeneity in a Klebsiella pneumoniae strain isolated from a primary liver abscess. J. Bacteriol. 190, 515–526. doi: 10.1128/jb.01219-07,
Liu, Y.-C., Cheng, D.-L., and Lin, C.-L. (1986). Klebsiella pneumoniae liver abscess associated with septic endophthalmitis. Arch. Intern. Med. 146, 1913–1916. doi: 10.1001/archinte.1986.00360220057011,
Lu, M. C., Chen, Y. T., Chiang, M. K., Wang, Y. C., Hsiao, P. Y., Huang, Y. J., et al. (2017). Colibactin contributes to the hypervirulence of pks(+) K1 CC23 Klebsiella pneumoniae in mouse meningitis infections. Front. Cell. Infect. Microbiol. 7:103. doi: 10.3389/fcimb.2017.00103,
Lu, Y., Feng, Y., McNally, A., and Zong, Z. (2018). Occurrence of colistin-resistant hypervirulent Klebsiella variicola. J. Antimicrob. Chemother. 73, 3001–3004. doi: 10.1093/jac/dky301,
Marcoleta, A. E., Berríos-Pastén, C., Nuñez, G., Monasterio, O., and Lagos, R. (2016). Klebsiella pneumoniae asparagine tDNAs are integration hotspots for different Genomic Islands encoding microcin E492 production determinants and other putative virulence factors present in hypervirulent strains. Front. Microbiol. 7:849. doi: 10.3389/fmicb.2016.00849,
Meng, J., Young, G., and Chen, J. (2021). The Rcs system in Enterobacteriaceae: envelope stress responses and virulence regulation. Front. Microbiol. 12:627104. doi: 10.3389/fmicb.2021.627104,
Müller, S. I., Valdebenito, M., and Hantke, K. (2009). Salmochelin, the long-overlooked catecholate siderophore of Salmonella. Biometals 22, 691–695. doi: 10.1007/s10534-009-9217-4,
Nassif, X., Fournier, J. M., Arondel, J., and Sansonetti, P. J. (1989). Mucoid phenotype of Klebsiella pneumoniae is a plasmid-encoded virulence factor. Infect. Immun. 57, 546–552. doi: 10.1128/iai.57.2.546-552.1989,
Nassif, X., and Sansonetti, P. J. (1986). Correlation of the virulence of Klebsiella pneumoniae K1 and K2 with the presence of a plasmid encoding aerobactin. Infect. Immun. 54, 603–608. doi: 10.1128/iai.54.3.603-608.1986,
Nguyen, Q., Nguyen, Y. T. P., Ha, T. T., Tran, D. T. N., Voong, P. V., Chau, V., et al. (2024). Genomic insights unveil the plasmid transfer mechanism and epidemiology of hypervirulent Klebsiella pneumoniae in Vietnam. Nat. Commun. 15:4187. doi: 10.1038/s41467-024-48206-3,
Nicolas, E., Lambin, M., Dandoy, D., Galloy, C., Nguyen, N., Oger, C. A., et al. (2015). The Tn3-family of replicative transposons. Microbiol. Spectr. 3:10-1128. doi: 10.1128/microbiolspec.MDNA3-0060-2014,
Paauw, A., Leverstein-van Hall, M. A., Verhoef, J., and Fluit, A. C. (2010). Evolution in quantum leaps: multiple combinatorial transfers of HPI and other genetic modules in Enterobacteriaceae. PLoS One 5:e8662. doi: 10.1371/journal.pone.0008662,
Paczosa, M. K., and Mecsas, J. (2016). Klebsiella pneumoniae: going on the offense with a strong Defense. Microbiol. Mol. Biol. Rev. 80, 629–661. doi: 10.1128/mmbr.00078-15,
Palacios, M., Miner, T. A., Frederick, D. R., Sepulveda, V. E., Quinn, J. D., Walker, K. A., et al. (2018). Identification of two regulators of virulence that are conserved in Klebsiella pneumoniae classical and hypervirulent strains. mBio 9:e01443-18. doi: 10.1128/mBio.01443-18,
Putze, J., Hennequin, C., Nougayrède, J. P., Zhang, W., Homburg, S., Karch, H., et al. (2009). Genetic structure and distribution of the colibactin genomic island among members of the family Enterobacteriaceae. Infect. Immun. 77, 4696–4703. doi: 10.1128/iai.00522-09,
Ramirez, M. S., Traglia, G. M., Lin, D. L., Tran, T., and Tolmasky, M. E. (2014). Plasmid-mediated antibiotic resistance and virulence in gram-negatives: the Klebsiella pneumoniae paradigm. Microbiol. Spectr. 2, 1–15. doi: 10.1128/microbiolspec.PLAS-0016-2013,
Roulston, K. J., Bharucha, T., Turton, J. F., Hopkins, K. L., and Mack, D. J. F. (2018). A case of NDM-carbapenemase-producing hypervirulent Klebsiella pneumoniae sequence type 23 from the UK. JMM Case Rep. 5:e005130. doi: 10.1099/jmmcr.0.005130,
Russo, T. A., and Marr, C. M. (2019). Hypervirulent Klebsiella pneumoniae. Clin. Microbiol. Rev. 32:e00001-19. doi: 10.1128/cmr.00001-19,
Russo, T. A., Olson, R., MacDonald, U., Beanan, J., and Davidson, B. A. (2015). Aerobactin, but not yersiniabactin, salmochelin, or enterobactin, enables the growth/survival of hypervirulent (hypermucoviscous) Klebsiella pneumoniae ex vivo and in vivo. Infect. Immun. 83, 3325–3333. doi: 10.1128/iai.00430-15,
Russo, T. A., Olson, R., Macdonald, U., Metzger, D., Maltese, L. M., Drake, E. J., et al. (2014). Aerobactin mediates virulence and accounts for increased siderophore production under iron-limiting conditions by hypervirulent (hypermucoviscous) Klebsiella pneumoniae. Infect. Immun. 82, 2356–2367. doi: 10.1128/iai.01667-13,
Sati, H., Carrara, E., Savoldi, A., Hansen, P., Garlasco, J., Campagnaro, E., et al. (2025). The WHO bacterial priority pathogens list 2024: a prioritisation study to guide research, development, and public health strategies against antimicrobial resistance. Lancet Infect. Dis. 25, 1033–1043. doi: 10.1016/S1473-3099(25)00118-5,
Schalk, I. J. (2025). Bacterial siderophores: diversity, uptake pathways and applications. Nat. Rev. Microbiol. 23, 24–40. doi: 10.1038/s41579-024-01090-6,
Shon, A. S., and Russo, T. A. (2012). Hypervirulent Klebsiella pneumoniae: the next superbug? Future Microbiol. 7, 669–671. doi: 10.2217/fmb.12.43,
Struve, C., Roe, C. C., Stegger, M., Stahlhut, S. G., Hansen, D. S., Engelthaler, D. M., et al. (2015). Mapping the evolution of hypervirulent Klebsiella pneumoniae. mBio 6:e00630. doi: 10.1128/mBio.00630-15,
Tian, T., Han, H., Guan, Z.-H., Zhang, K., Huang, X., Wang, W., et al. (2025). A systematic review of hypervirulent Klebsiella pneumoniae research: bibliometric and topic modeling perspectives. Front. Med. 12:1545678. doi: 10.3389/fmed.2025.1545678,
Tian, C., Xing, M., Zhao, Y., Fan, X., Bai, Y., Fu, L., et al. (2022). Whole genome sequencing of OXA-232-producing wzi93-KL112-O1 carbapenem-resistant Klebsiella pneumoniae in human bloodstream infection co-harboring chromosomal ISEcp1-based Bla (CTX-M-15) and one rmpA2-associated virulence plasmid. Front. Cell. Infect. Microbiol. 12:984479. doi: 10.3389/fcimb.2022.984479,
Tian, D., Zhao, M., Zheng, S., Jiang, X., and Zhang, B. (2023). Involvement of Tn3 transposon in formation and transmission of hypervirulent and carbapenem-resistant Klebsiella pneumoniae. Microbiol. Spectr. 11:e0303823. doi: 10.1128/spectrum.03038-23,
Tu, Y. C., Lu, M. C., Chiang, M. K., Huang, S. P., Peng, H. L., Chang, H. Y., et al. (2009). Genetic requirements for Klebsiella pneumoniae-induced liver abscess in an oral infection model. Infect. Immun. 77, 2657–2671. doi: 10.1128/iai.01523-08,
Wacharotayankun, R., Arakawa, Y., Ohta, M., Tanaka, K., Akashi, T., Mori, M., et al. (1993). Enhancement of extracapsular polysaccharide synthesis in klebsiella-pneumoniae by rmpa2, which shows homology to ntrc and fixj. Infect. Immun. 61, 3164–3174. doi: 10.1128/iai.61.8.3164-3174.1993,
Walker Kimberly, A., Miner Taryn, A., Palacios, M., Trzilova, D., Frederick Daniel, R., Broberg Christopher, A., et al. (2019). A Klebsiella pneumoniae regulatory mutant has reduced capsule expression but retains hypermucoviscosity. MBio 10:e00089-19. doi: 10.1128/mbio.00089-19
Walker Kimberly, A., Treat Logan, P., Sepúlveda Victoria, E., and Miller Virginia, L. (2020). The small protein RmpD drives hypermucoviscosity in Klebsiella pneumoniae. MBio 11:e01750-20. doi: 10.1128/mbio.01750-20,
Wang, S., Ding, Q., Zhang, Y., Zhang, A., Wang, Q., Wang, R., et al. (2022). Evolution of virulence, fitness, and carbapenem resistance transmission in ST23 hypervirulent Klebsiella pneumoniae with the capsular polysaccharide synthesis gene wcaJ inserted via insertion sequence elements. Microbiol. Spectr. 10:e0240022. doi: 10.1128/spectrum.02400-22,
Wang, Q., Liu, Y., Chen, R., Zhang, M., Si, Z., Wang, Y., et al. (2024). Genomic insights into the evolution and mechanisms of carbapenem-resistant hypervirulent Klebsiella pneumoniae co-harboring Bla(KPC) and Bla(NDM): implications for public health threat mitigation. Ann. Clin. Microbiol. Antimicrob. 23:27. doi: 10.1186/s12941-024-00686-3,
Wang, S., Ma, S., Sun, S., Wang, Q., Ding, Q., Jin, L., et al. (2024). Global evolutionary dynamics of virulence genes in ST11-KL47 carbapenem-resistant Klebsiella pneumoniae. Int. J. Antimicrob. Agents 64:107245. doi: 10.1016/j.ijantimicag.2024.107245,
Wei, D. W., Song, Y., Li, Y., Zhang, G., Chen, Q., Wu, L., et al. (2025). Insertion sequences accelerate genomic convergence of multidrug resistance and hypervirulence in Klebsiella pneumoniae via capsular phase variation. Genome Med. 17:45. doi: 10.1186/s13073-025-01474-0,
Wu, K., Lin, X., Lu, Y., Dong, R., Jiang, H., Svensson, S. L., et al. (2024). RNA interactome of hypervirulent Klebsiella pneumoniae reveals a small RNA inhibitor of capsular mucoviscosity and virulence. Nat. Commun. 15:6946. doi: 10.1038/s41467-024-51213-z,
Wyres, K. L., Wick, R. R., Judd, L. M., Froumine, R., Tokolyi, A., Gorrie, C. L., et al. (2019). Distinct evolutionary dynamics of horizontal gene transfer in drug resistant and virulent clones of Klebsiella pneumoniae. PLoS Genet. 15:e1008114. doi: 10.1371/journal.pgen.1008114,
Xu, L., Li, J., Wu, W., Wu, X., and Ren, J. (2024). Klebsiella pneumoniae capsular polysaccharide: mechanism in regulation of synthesis, virulence, and pathogenicity. Virulence 15:2439509. doi: 10.1080/21505594.2024.2439509,
Yang, X., Dong, N., Chan, E. W., Zhang, R., and Chen, S. (2021). Carbapenem resistance-encoding and virulence-encoding conjugative plasmids in Klebsiella pneumoniae. Trends Microbiol. 29, 65–83. doi: 10.1016/j.tim.2020.04.012,
Yang, X., Wai-Chi Chan, E., Zhang, R., and Chen, S. (2019). A conjugative plasmid that augments virulence in Klebsiella pneumoniae. Nat. Microbiol. 4, 2039–2043. doi: 10.1038/s41564-019-0566-7,
Yuan, L., Li, X., Du, L., Su, K., Zhang, J., Liu, P., et al. (2020). RcsAB and Fur coregulate the iron-acquisition system via entC in Klebsiella pneumoniae NTUH-K2044 in response to iron availability. Front. Cell. Infect. Microbiol. 10:282. doi: 10.3389/fcimb.2020.00282,
Zhu, Q., Lin, Q., Jiang, Y., Chen, S., Tian, J., Yang, S., et al. (2023). Construction and application of the conditionally essential gene knockdown library in Klebsiella pneumoniae to screen potential antimicrobial targets and virulence genes via Mobile-CRISPRi-seq. Appl. Environ. Microbiol. 89, e0095623–e0000923. doi: 10.1128/aem.00956-23,
Keywords: integrative conjugative element, Klebsiella pneumoniae, mobile genetic elements, pathogenicity, plasmid, virulence
Citation: Li Y and Farzana R (2026) Mobile genetic elements in shaping Klebsiella pneumoniae pathogenicity. Front. Microbiol. 16:1730961. doi: 10.3389/fmicb.2025.1730961
Edited by:
Axel Cloeckaert, Institut National de recherche pour l’agriculture, l’alimentation et l’environnement (INRAE), FranceReviewed by:
Anand Bahadur Karki, Sam Houston State University, United StatesJonathan Rodriguez-Santiago, Autonomous University of Chiapas, Mexico
Copyright © 2026 Li and Farzana. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Yanbing Li, eWFuYmluZy5saUBiaW9sb2d5Lm94LmFjLnVr; Refath Farzana, cmVmYXRoLmZhcnphbmFAYmlvbG9neS5veC5hYy51aw==
†These authors have contributed equally to this work