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Open AccessOpen Access JUSTC Life Sciences 28 September 2023

An abnormal multidrug-resistant and hypervirulent Klebsiella pneumoniae clinical isolate without rmpA or rmpA2

  • 1.

    Department of Oncology, the First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230027, China

  • 2.

    School of the Gifted Young, University of Science and Technology of China, Hefei 230026, China

  • 3.

    Department of Clinical Laboratory, the First Affiliated Hospital of USTC, Hefei 230001, China

Cite this:
https://doi.org/10.52396/JUSTC-2023-0085
More Information
  • Author Bio:

    Zhien He is currently a doctoral candidate in the Division of Life Sciences and Medicine, University of Science and Technology of China, under the supervision of Prof. Baolin Sun. His research mainly focuses on the epidemiology of hypervirulent Klebsiella pneumoniae and Acinetobacter baumannii

    Baolin Sun is a Professor at the University of Science and Technology of China. He received his Ph.D. degree from Michigan State University in 1999. In 2004, he was selected into the Hundred Talents Program of the Chinese Academy of Sciences. His research interests include the expression regulation of virulence genes of pathogens, the regulatory mechanisms of the occurrence and transfer of bacterial resistance, and the interaction mechanisms between pathogens and hosts

    Yujie Li is currently an Associate Research Fellow at the University of Science and Technology of China. He received his Ph.D. degree in Microbiology from Southwest University in 2020 under the supervision of Prof. Yan Pei. He then joined Prof. Baolin Sun’s group as a postdoctoral fellow in July 2020. His scientific interests include the bacterial drug resistance and pathogenicity and bacteria-host interaction

  • Corresponding author: E-mail: sunb@ustc.edu.cn; E-mail: lyj2020@ustc.edu.cn
  • Received Date: 08 May 2023
  • Accepted Date: 21 July 2023
    • Available Online: 28 September 2023
    Abstract

  • Abstract

    Klebsiella pneumoniae is a notorious opportunistic pathogen, especially hypervirulent K. pneumoniae (hvKp). Fortunately, most classical hvKp strains are antibiotic-susceptible. However, in recent years, reports of multidrug-resistant hvKp (MDR-hvKp) have increased dramatically, threatening the health and safety of people worldwide. Here, we report the discovery of MDR-hvKp without rmpA and rmpA2 in a 92-year-old patient with chronic obstructive pulmonary disease. The patient died on the eighth day of hospitalization. Phenotyping experiments and whole-genome sequencing of K. pneumoniae isolate 21072329 isolated from the patient’s sputum were performed. Moreover, 21072329 belongs to ST11-KL47 MDR-hvKp, which was highly lethal to Galleria mellonella. Meanwhile, 21072329 had a strong viscosity, and it was difficult to completely centrifuge it; 21072329 carried ESBL genes (blaCTX-M-65, blaSHV-158, and blaTEM-1) and a carbapenemase gene (blaKPC-2), and it was resistant to carbapenem antibiotics and third- and fourth-generation cephalosporins. Although 21072329 had the characteristics of hvKp, rmpA and rmpA2 could not be found in its genome; it also only carried a siderophore of yersiniabactin. This may indicate that other hypervirulence factors promote the formation of hvKp. MDR-hvKp has already brought an enormous burden to global medical care, and those carrying unknown hypervirulence factors are new threats, so urgent prevention and control with research are urgently needed.

    Graphical abstract

    Multidrug-resistant hypervirulence Klebsiella pneumoniae 21072329 without rmpA and rmpA2 isolated from the sputum of patients with chronic obstructive pulmonary disease.

    Abstract

    Klebsiella pneumoniae is a notorious opportunistic pathogen, especially hypervirulent K. pneumoniae (hvKp). Fortunately, most classical hvKp strains are antibiotic-susceptible. However, in recent years, reports of multidrug-resistant hvKp (MDR-hvKp) have increased dramatically, threatening the health and safety of people worldwide. Here, we report the discovery of MDR-hvKp without rmpA and rmpA2 in a 92-year-old patient with chronic obstructive pulmonary disease. The patient died on the eighth day of hospitalization. Phenotyping experiments and whole-genome sequencing of K. pneumoniae isolate 21072329 isolated from the patient’s sputum were performed. Moreover, 21072329 belongs to ST11-KL47 MDR-hvKp, which was highly lethal to Galleria mellonella. Meanwhile, 21072329 had a strong viscosity, and it was difficult to completely centrifuge it; 21072329 carried ESBL genes (blaCTX-M-65, blaSHV-158, and blaTEM-1) and a carbapenemase gene (blaKPC-2), and it was resistant to carbapenem antibiotics and third- and fourth-generation cephalosporins. Although 21072329 had the characteristics of hvKp, rmpA and rmpA2 could not be found in its genome; it also only carried a siderophore of yersiniabactin. This may indicate that other hypervirulence factors promote the formation of hvKp. MDR-hvKp has already brought an enormous burden to global medical care, and those carrying unknown hypervirulence factors are new threats, so urgent prevention and control with research are urgently needed.

    • Public Summary

    • A fatal multidrug-resistant hypervirulent K. pneumoniae, 21072329, was reported.
    • Multidrug-resistant hypervirulent K. pneumoniae 21072329 without rmpA and rmpA2.
    • Multidrug-resistant hypervirulent K. pneumoniae 21072329 carried only one siderophore of yersiniabactin.

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    • References(22)
  • [1]
    Liu Y C, Cheng D L, Lin C L. Klebsiella pneumoniae liver abscess associated with septic endophthalmitis. Arch. Intern. Med., 1986, 146 (10): 1913–1916. doi: 10.1001/archinte.1986.00360220057011
    [2]
    Russo T A, Marr C M. Hypervirulent Klebsiella pneumoniae. Clin. Microbiol. Rev., 2019, 32 (3): e00001–e00019. doi: 10.1128/CMR.00001-19
    [3]
    Dong N, Yang X M, Chan E W C, et al. Klebsiella species: Taxonomy, hypervirulence and multidrug resistance. EBioMedicine, 2022, 79: 103998. doi: 10.1016/j.ebiom.2022.103998
    [4]
    Fang C T, Chuang Y P, Shun C T, et al. A novel virulence gene in Klebsiella pneumoniae strains causing primary liver abscess and septic metastatic complications. J. Exp. Med., 2004, 199 (5): 697–705. doi: 10.1084/jem.20030857
    [5]
    Lin Y C, Lu M C, Tang H L, et al. Assessment of hypermucoviscosity as a virulence factor for experimental Klebsiella pneumoniae infections: comparative virulence analysis with hypermucoviscosity-negative strain. BMC Microbiol., 2011, 11: 50. doi: 10.1186/1471-2180-11-50
    [6]
    Russo T A, Olson R, Fang C T, et al. Identification of biomarkers for differentiation of hypervirulent Klebsiella pneumoniae from classical K. pneumoniae. J. Clin. Microbiol., 2018, 56 (9): e00776–e00718. doi: 10.1128/JCM.00776-18
    [7]
    Brisse S, Fevre C, Passet V, et al. Virulent clones of Klebsiella pneumoniae: Identification and evolutionary scenario based on genomic and phenotypic characterization. PLos ONE, 2009, 4 (3): e4982. doi: 10.1371/journal.pone.0004982
    [8]
    Choby J E, Howard-Anderson J, Weiss D S. Hypervirulent Klebsiella pneumoniae – clinical and molecular perspectives. J. Intern. Med., 2020, 287 (3): 283–300. doi: 10.1111/joim.13007
    [9]
    Wu Y, Wu C, Bao D, et al. Global evolution and geographic diversity of hypervirulent carbapenem-resistant Klebsiella pneumoniae. Lancet Infect. Dis., 2022, 22 (6): 761–762. doi: 10.1016/S1473-3099(22)00275-4
    [10]
    Rossi B, Gasperini M L, Leflon-Guibout V, et al. Hypervirulent Klebsiella pneumoniae in cryptogenic liver abscesses, Paris, France. Emerg. Infect. Dis., 2018, 24 (2): 221–229. doi: 10.3201/eid2402.170957
    [11]
    Lin Y T, Cheng Y H, Juan C H, et al. High mortality among patients infected with hypervirulent antimicrobial-resistant capsular type K1 Klebsiella pneumoniae strains in Taiwan. Int. J. Antimicrob. Ag., 2018, 52 (2): 251–257. doi: 10.1016/j.ijantimicag.2018.06.008
    [12]
    Tabrizi A M A, Badmasti F, Shahcheraghi F, et al. Outbreak of hypervirulent Klebsiella pneumoniae harbouring blaVIM-2 among mechanically-ventilated drug-poisoning patients with high mortality rate in Iran. J. Glob. Antimicrob. Re., 2018, 15: 93–98. doi: 10.1016/j.jgar.2018.06.020
    [13]
    He Z, Yang Y, Li W, et al. Comparative genomic analyses of Polymyxin-resistant Enterobacteriaceae strains from China. BMC Genomics, 2022, 23 (1): 88. doi: 10.1186/s12864-022-08301-5
    [14]
    Wu K M, Li L H, Yan J J, et al. Genome sequencing and comparative analysis of Klebsiella pneumoniae NTUH-K2044, a strain causing liver abscess and meningitis. J. Bacteriol., 2009, 191 (14): 4492–4501. doi: 10.1128/JB.00315-09
    [15]
    Wick R R, Judd L M, Gorrie C L, et al. Unicycler: Resolving bacterial genome assemblies from short and long sequencing reads. PLoS Comput. Biol., 2017, 13 (6): e1005595. doi: 10.1371/journal.pcbi.1005595
    [16]
    Bankevich A, Nurk S, Antipov D, et al. SPAdes: A new genome assembly algorithm and its applications to single-cell sequencing. J. Comput. Biol., 2012, 19 (5): 455–477. doi: 10.1089/cmb.2012.0021
    [17]
    Seemann T. Prokka: rapid prokaryotic genome annotation. Bioinformatics, 2014, 30 (14): 2068–2069. doi: 10.1093/bioinformatics/btu153
    [18]
    Alikhan N F, Petty N K, Ben Zakour N L, et al. BLAST Ring Image Generator (BRIG): simple prokaryote genome comparisons. BMC Genomics, 2011, 12: 402. doi: 10.1186/1471-2164-12-402
    [19]
    Zankari E, Hasman H, Cosentino S, et al. Identification of acquired antimicrobial resistance genes. J. Antimicrob. Chemother., 2012, 67 (11): 2640–2644. doi: 10.1093/jac/dks261
    [20]
    Wyres K L, Wick R R, Gorrie C, et al. Identification of Klebsiella capsule synthesis loci from whole genome data. Microb. Genomics, 2016, 2 (12): e000102. doi: 10.1099/mgen.0.000102
    [21]
    He Z, Xu W, Zhao H, et al. Epidemiological characteristics an outbreak of ST11 multidrug-resistant and hypervirulent Klebsiella pneumoniae in Anhui, China. Front. Microbiol., 2022, 13: 996753. doi: 10.3389/fmicb.2022.996753
    [22]
    Altayb H N, Elbadawi H S, Baothman O, et al. Genomic analysis of multidrug-resistant hypervirulent (hypermucoviscous) Klebsiella pneumoniae strain lacking the hypermucoviscous regulators (rmpA/rmpA2). Antibiotics., 2022, 11 (5): 596. doi: 10.3390/antibiotics11050596
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    Figure  1.  Clinical data of the patient infected with 21072329 and genetic features of the genome and ESBL plasmid (p21072329_1) of K. pneumoniae isolate 21072329. (a) Time and site of K. pneumoniae isolation from patients infected with 21072329 and antibiotic treatment. (b) Chromosome map of 21072329. Different types of functional genes are indicated by different colors. (c) Plasmid map of p21072329_2 using a BLAST Ring Image Generator. Drug resistance genes are indicated by red, transposons are indicated by green, virulence factors are indicated by purple, genes of unknown function are indicated by gray, and other genes are indicated by orange.

    Figure  2.  K. pneumoniae isolate 21072329 showed high virulence and high visibility. The G. mellonella infection model was used to evaluate the virulence of strains at three different concentrations (1×106 CFU: (a); 1×105 CFU: (b); 1×104 CFU: (c)). Their viscosity was evaluated by measuring the OD600 of the supernatant after centrifugation (initial OD600 adjusted to 1: (d); initial OD600 adjusted to 2: (e); initial OD600 adjusted to 3: (f)). *P < 0.05, ** P < 0.01, *** P < 0.001, ns: no significant difference.

    [1]
    Liu Y C, Cheng D L, Lin C L. Klebsiella pneumoniae liver abscess associated with septic endophthalmitis. Arch. Intern. Med., 1986, 146 (10): 1913–1916. doi: 10.1001/archinte.1986.00360220057011
    [2]
    Russo T A, Marr C M. Hypervirulent Klebsiella pneumoniae. Clin. Microbiol. Rev., 2019, 32 (3): e00001–e00019. doi: 10.1128/CMR.00001-19
    [3]
    Dong N, Yang X M, Chan E W C, et al. Klebsiella species: Taxonomy, hypervirulence and multidrug resistance. EBioMedicine, 2022, 79: 103998. doi: 10.1016/j.ebiom.2022.103998
    [4]
    Fang C T, Chuang Y P, Shun C T, et al. A novel virulence gene in Klebsiella pneumoniae strains causing primary liver abscess and septic metastatic complications. J. Exp. Med., 2004, 199 (5): 697–705. doi: 10.1084/jem.20030857
    [5]
    Lin Y C, Lu M C, Tang H L, et al. Assessment of hypermucoviscosity as a virulence factor for experimental Klebsiella pneumoniae infections: comparative virulence analysis with hypermucoviscosity-negative strain. BMC Microbiol., 2011, 11: 50. doi: 10.1186/1471-2180-11-50
    [6]
    Russo T A, Olson R, Fang C T, et al. Identification of biomarkers for differentiation of hypervirulent Klebsiella pneumoniae from classical K. pneumoniae. J. Clin. Microbiol., 2018, 56 (9): e00776–e00718. doi: 10.1128/JCM.00776-18
    [7]
    Brisse S, Fevre C, Passet V, et al. Virulent clones of Klebsiella pneumoniae: Identification and evolutionary scenario based on genomic and phenotypic characterization. PLos ONE, 2009, 4 (3): e4982. doi: 10.1371/journal.pone.0004982
    [8]
    Choby J E, Howard-Anderson J, Weiss D S. Hypervirulent Klebsiella pneumoniae – clinical and molecular perspectives. J. Intern. Med., 2020, 287 (3): 283–300. doi: 10.1111/joim.13007
    [9]
    Wu Y, Wu C, Bao D, et al. Global evolution and geographic diversity of hypervirulent carbapenem-resistant Klebsiella pneumoniae. Lancet Infect. Dis., 2022, 22 (6): 761–762. doi: 10.1016/S1473-3099(22)00275-4
    [10]
    Rossi B, Gasperini M L, Leflon-Guibout V, et al. Hypervirulent Klebsiella pneumoniae in cryptogenic liver abscesses, Paris, France. Emerg. Infect. Dis., 2018, 24 (2): 221–229. doi: 10.3201/eid2402.170957
    [11]
    Lin Y T, Cheng Y H, Juan C H, et al. High mortality among patients infected with hypervirulent antimicrobial-resistant capsular type K1 Klebsiella pneumoniae strains in Taiwan. Int. J. Antimicrob. Ag., 2018, 52 (2): 251–257. doi: 10.1016/j.ijantimicag.2018.06.008
    [12]
    Tabrizi A M A, Badmasti F, Shahcheraghi F, et al. Outbreak of hypervirulent Klebsiella pneumoniae harbouring blaVIM-2 among mechanically-ventilated drug-poisoning patients with high mortality rate in Iran. J. Glob. Antimicrob. Re., 2018, 15: 93–98. doi: 10.1016/j.jgar.2018.06.020
    [13]
    He Z, Yang Y, Li W, et al. Comparative genomic analyses of Polymyxin-resistant Enterobacteriaceae strains from China. BMC Genomics, 2022, 23 (1): 88. doi: 10.1186/s12864-022-08301-5
    [14]
    Wu K M, Li L H, Yan J J, et al. Genome sequencing and comparative analysis of Klebsiella pneumoniae NTUH-K2044, a strain causing liver abscess and meningitis. J. Bacteriol., 2009, 191 (14): 4492–4501. doi: 10.1128/JB.00315-09
    [15]
    Wick R R, Judd L M, Gorrie C L, et al. Unicycler: Resolving bacterial genome assemblies from short and long sequencing reads. PLoS Comput. Biol., 2017, 13 (6): e1005595. doi: 10.1371/journal.pcbi.1005595
    [16]
    Bankevich A, Nurk S, Antipov D, et al. SPAdes: A new genome assembly algorithm and its applications to single-cell sequencing. J. Comput. Biol., 2012, 19 (5): 455–477. doi: 10.1089/cmb.2012.0021
    [17]
    Seemann T. Prokka: rapid prokaryotic genome annotation. Bioinformatics, 2014, 30 (14): 2068–2069. doi: 10.1093/bioinformatics/btu153
    [18]
    Alikhan N F, Petty N K, Ben Zakour N L, et al. BLAST Ring Image Generator (BRIG): simple prokaryote genome comparisons. BMC Genomics, 2011, 12: 402. doi: 10.1186/1471-2164-12-402
    [19]
    Zankari E, Hasman H, Cosentino S, et al. Identification of acquired antimicrobial resistance genes. J. Antimicrob. Chemother., 2012, 67 (11): 2640–2644. doi: 10.1093/jac/dks261
    [20]
    Wyres K L, Wick R R, Gorrie C, et al. Identification of Klebsiella capsule synthesis loci from whole genome data. Microb. Genomics, 2016, 2 (12): e000102. doi: 10.1099/mgen.0.000102
    [21]
    He Z, Xu W, Zhao H, et al. Epidemiological characteristics an outbreak of ST11 multidrug-resistant and hypervirulent Klebsiella pneumoniae in Anhui, China. Front. Microbiol., 2022, 13: 996753. doi: 10.3389/fmicb.2022.996753
    [22]
    Altayb H N, Elbadawi H S, Baothman O, et al. Genomic analysis of multidrug-resistant hypervirulent (hypermucoviscous) Klebsiella pneumoniae strain lacking the hypermucoviscous regulators (rmpA/rmpA2). Antibiotics., 2022, 11 (5): 596. doi: 10.3390/antibiotics11050596
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