Carbapenem Resistance-Encoding and Virulence-Encoding Conjugative Plasmids in Klebsiella pneumoniae

doi:10.1016/j.tim.2020.04.012

Trends in Microbiology

Volume 29, Issue 1, January 2021, Pages 65-83

https://doi.org/10.1016/j.tim.2020.04.012 Get rights and content

Highlights

K. pneumoniae has become one of the most important bacterial pathogens; it causes a high mortality rate in patients.
K. pneumoniae has an exceptional ability to acquire exogenous resistance-encoding and hypervirulence-encoding genetic elements, and it has evolved rapidly in the past decade.
In one evolutionary route, classical K. pneumoniae strains acquired different types of bla_KPC-encoding plasmid and evolved to become carbapenem-resistant K. pneumoniae (CRKP).
In another evolutionary route, classical K. pneumoniae strains have become hypervirulent K. pneumoniae (hvKP) through the acquisition of pLVPK-like virulence plasmids.
One important evolutionary feature of these plasmids is that they contain a wide range of transposable elements that enable them to undergo frequent genetic transposition, resulting in plasmid fusion and presumably better adaptation of the plasmid to the bacterial host.
In recent years, convergence of these two evolutionary paths has been observed in K. pneumoniae, resulting in the emergence of carbapenem-resistant and hypervirulent K. pneumoniae (CR-hvKP) due to plasmid recombination and fusion processes.
Identifying the key molecular markers of resistance and virulence-bearing conjugative plasmids allows improved tracking and control of the life-threatening carbapenem-resistant and hypervirulent strains of K. pneumoniae.

Klebsiella pneumoniae has an exceptional ability to acquire exogenous resistance-encoding and hypervirulence-encoding genetic elements. In this review we trace the key evolutionary routes of plasmids involved in the dissemination of such elements; we observed diverse, but convergent, evolutionary paths that eventually led to the emergence of conjugative plasmids which simultaneously encode carbapenem resistance and hypervirulence. One important evolutionary feature of these plasmids is that they contain a wide range of transposable elements that enable them to undergo frequent genetic transposition, resulting in plasmid fusion and presumably better adaptation of the plasmid to the bacterial host. Identifying the key molecular markers of resistance and virulence-bearing conjugative plasmids allows improved tracking and control of the life-threatening carbapenem-resistant and hypervirulent strains of K. pneumoniae.

Introduction

K. pneumoniae is a human commensal and opportunistic pathogen that can cause severe hospital-acquired infections, especially among patients with compromised immune systems [1]. Since the 1980s, however, K. pneumoniae has also been known to cause community-acquired infections among young and relatively healthy individuals [2]. K. pneumoniae strains causing such invasive infections are termed hypervirulent K. pneumoniae (hvKP) [3]. The emergence of hvKP strains heralded the onset of a new and rapidly worsening public health disaster on a global scale [2]. hvKP is known to contain a typical ~200 kb virulence plasmid which harbors a number of virulence-encoding genes; such plasmids were found to undergo constant genetic changes during the transmission process, suggesting that they have adapted rapidly to coexist with strains of K. pneumoniae of different genetic types [4,5]. Furthermore, the genome of K. pneumoniae continues to receive antibiotic-resistance genes by acquiring plasmids and transferable genetic elements, resulting in the emergence of multidrug-resistant (MDR) and extremely-drug-resistant (XDR) strains [6,7]. The latest World Health Organization (WHO) antimicrobial resistance surveillance report announced that carbapenem-resistant K. pneumoniae (CRKP) strains have appeared in all WHO regions, with some exhibiting a prevalence of >50% [8]. For a long period of time, K. pneumoniae did not simultaneously encode the phenotypes of MDR and hypervirulence. Strains of MDR K. pneumoniae (MDR-KP) belong mainly in clonal groups (CGs) 258, 15, and 147, whereas strains of hvKP belong mainly in CGs 23, 86, and 380 and are mainly K1 and K2 serotypes [9]. The molecular basis of the discrepancy between the genetic background of hvKP and MDR-KP strains remains unknown. However, antibiotic-resistant hvKP isolates have become increasingly prevalent worldwide in the past few years [10,11]. Conjugative plasmids, which are mobile genetic elements responsible for disseminating resistance and virulence-encoding genes, are the main culprit driving the evolution of K. pneumoniae. In this review we trace the key evolutionary routes of plasmids which encode resistance and virulence in K. pneumoniae, provide an overview of the variety and genetic features of resistance and virulence plasmids recovered at various stages of such evolutionary routes, and discuss the clinical significance of such plasmids.

Section snippets

Conjugative Plasmids Encoding Resistance to Carbapenems

The extensive use of carbapenems has led to the selection, evolution, and widespread dissemination of strains of the family Enterobacteriaceae that harbor carbapenemase-encoding plasmids, among which Klebsiella has become the major carbapenem-resistant Enterobacteriaceae (CRE) species. The first strain of CRKP, which was isolated as early as 1985 in Germany, was resistant to imipenem as well as to third-generation cephalosporins [12]. The earliest detectable carbapenemase was IMP-1, which was

Nonconjugative Virulence Plasmids in hvKP

Strains of hvKP are known to contain a typical ~200 kb virulence plasmid which harbors a number of virulence-encoding genes, including mucoid phenotype regulator genes (rmpA and rmpA2), and siderophore (aerobactin and salmochelin)-encoding gene clusters. Such plasmids were found to be nonconjugative due to a lack of the plasmid-transfer genes. hvKP was first recognized during a clinical investigation in 1986, which reported seven cases of invasive K. pneumoniae infection in Taiwan in which

Conjugative Virulence Plasmids in hvKP

The initially identified virulence plasmids, such as pLVPK and pK2044, lack the tra genes and are nonconjugative, yet plasmid recombination between pLVPK and other plasmids is increasingly being observed (Figure 3B and Table 2). A hybrid virulence plasmid, pVir (297 984 bp), has been recovered from an ST11 strain, TVGHCRE225, which is resistant to carbapenem, tigecycline, and colistin [59]. This plasmid is a hybrid of a pK2044-like virulence plasmid and a pPMK-NDM-like resistance plasmid.

Evolution of carbapenem-resistant and Hypervirulent K. pneumoniae

The phenotypes of MDR and hypervirulence in K. pneumoniae had been nonoverlapping for a long period of time as MDR phenotypes are often exhibited by cKP strains, whereas the carriage of MDR genes in hvKP isolates was rare [65]. However, carbapenem‐resistant hvKP isolates have been increasingly reported in recent years [10]. An analysis of more than 2200 K. pneumoniae strains conducted by Wyres et al. identified eight MDR and six hypervirulent clones [9]; their data also indicated that MDR

Concluding Remarks and Future Directions

K. pneumoniae is a high-risk clinical pathogen which has an exceptional ability to acquire multidrug resistance and hypervirulence-encoding mobile genetic elements. Carbapenem resistance in clinical strains are mediated mainly by KPC, NDM, and OXA-48-like carbpenemases, which are encoded by various plasmids (see Outstanding Questions). Transmission of bla_KPC-2 is generally mediated by two mobile elements: Tn4401 and NTE_KPC. Eight variants of Tn4401 and 24 variants of NTE_KPC have been identified

Acknowledgments

This study was funded by the Collaborative Research Fund from the Research Grant Council of the Government of Hong Kong SAR (C5026-16G), and the Research Impact Fund (R5011-18F).

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Trends in Microbiology

ReviewSpecial Issue: Microbial Genetics: Stress ManagementCarbapenem Resistance-Encoding and Virulence-Encoding Conjugative Plasmids in Klebsiella pneumoniae

Highlights

Introduction

Section snippets

Conjugative Plasmids Encoding Resistance to Carbapenems

Nonconjugative Virulence Plasmids in hvKP

Conjugative Virulence Plasmids in hvKP

Evolution of carbapenem-resistant and Hypervirulent K. pneumoniae

Concluding Remarks and Future Directions

Acknowledgments

Lancet Infect. Dis.

J. Glob Antimicrob. Resist.

Diagn. Microbiol. Infect. Dis.

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Gene

Int. J. Antimicrob. Agents

J. Infect.

J. Glob. Antimicrob. Resist.

Front. Public Health

BMC Microbiol.

Klebsiella pneumoniae: going on the offense with a strong defense

Microbiol. Mol. Biol. Rev.

Hypervirulent Klebsiella pneumoniae: the next superbug?

Future Microbiol.

Hypervirulent (hypermucoviscous) Klebsiella pneumoniae: a new and dangerous breed

Virulence

Comparative analysis of Klebsiella pneumoniae strains isolated in 2012–2016 that differ by antibiotic resistance genes and virulence genes profiles

Pathog. Glob. Health

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J. Clin. Microbiol.

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FEMS Microbiol. Rev.

Antimicrobial Resistance Global Report on Surveillance

Distinct evolutionary dynamics of horizontal gene transfer in drug resistant and virulent clones of Klebsiella pneumoniae

PLoS Genet.

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Eur. J. Clin. Microbiol. Infect. Dis.

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J. Antimicrob. Chemother.

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Antimicrob. Agents Chemother.

Novel carbapenem-hydrolyzing β-lactamase, KPC-1, from a carbapenem-resistant strain of Klebsiella pneumoniae

Antimicrob. Agents Chemother.

Molecular characterization of a cephamycin-hydrolyzing and inhibitor-resistant class A beta-lactamase, GES-4, possessing a single G170S substitution in the omega-loop

Antimicrob. Agents Chemother.

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J. Clin. Microbiol.

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Characterization of a new metallo-beta-lactamase gene, bla(NDM-1), and a novel erythromycin esterase gene carried on a unique genetic structure in Klebsiella pneumoniae sequence type 14 from India

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Antimicrob. Agents Chemother.

Complete nucleotide sequence of Klebsiella pneumoniae multidrug resistance plasmid pKP048, carrying blaKPC-2, blaDHA-1, qnrB4, and armA

Antimicrob. Agents Chemother.

Novel genetic environment of the carbapenem-hydrolyzing β-lactamase KPC-2 among Enterobacteriaceae in China

Antimicrob. Agents Chemother.

Comparative analysis of bla KPC-2- and rmtB-carrying IncFII-family pKPC-LK30/pHN7A8 hybrid plasmids from Klebsiella pneumoniae CG258 strains disseminated among multiple Chinese hospitals

Infect. Drug Resist.

Tracking microevolution events among ST11 carbapenemase-producing hypervirulent Klebsiella pneumoniae outbreak strains

Emerg. Microbes Infect.

Complete sequence of a novel IncR-F33:A-:B- plasmid, pKP1034, harboring fosA3, blaKPC-2, blaCTX-M-65, blaSHV-12, and rmtB from an epidemic Klebsiella pneumoniae sequence type 11 strain in China

Antimicrob. Agents Chemother.

An IncR plasmid harbored by a hypervirulent carbapenem-resistant Klebsiella pneumoniae strain possesses five tandem repeats of the bla KPC-2::NTEKPC-Id fragment

Antimicrob. Agents Chemother.

Complete nucleotide sequence of a blaKPC-harboring IncI2 plasmid and its dissemination in New Jersey and New York hospitals

Antimicrob. Agents Chemother.

Review
Special Issue: Microbial Genetics: Stress Management
Carbapenem Resistance-Encoding and Virulence-Encoding Conjugative Plasmids in Klebsiella pneumoniae

An IncR plasmid harbored by a hypervirulent carbapenem-resistant Klebsiella pneumoniae strain possesses five tandem repeats of the bla KPC-2::NTE_KPC-Id fragment