Taxonomic group: bacteria / Proteobacteria
(Phylum: Proteobacteria)
Host organism: Homo sapiens
Associated disease: pneumonia [ICD11:
CA40 
];
nosocomial infections [ICD11:
XB25 ];
osteomyelitis [ICD11:
FB84 ];
liver abscess [ICD11:
DB90.0 , ICD11:
SA04 ];
meningitis [ICD11:
1D01 ];
infection due to Klebsiella pneumoniae [ICD11:
XN741 ]
Publication DOI: 10.1073/pnas.1907833116Journal NLM ID: 7505876Publisher: National Academy of Sciences
Correspondence: christian.harding
vaxnewmo.com
Institutions: Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, MO 63110, VaxNewMo, St. Louis, MO 63108, Department of Microbiology and Immunology, The Peter Doherty Institute for Infection and Immunity, University of Melbourne, Parkville, Australia, Human Health Therapeutics, National Research Council Canada, Ottawa, ON K1A 0R6, Canada, Division of Pediatric Infectious Diseases, Department of Pediatrics, Washington University School of Medicine, St. Louis, MO 63110
Hypervirulent Klebsiella pneumoniae (hvKp) is globally disseminating as a community-acquired pathogen causing life-threatening infections in healthy individuals. The fact that a dose as little as 50 bacteria is lethal to mice illustrates the dramatic increase of virulence associated with hvKp strains compared with classical K. pneumoniae (cKp) strains, which require lethal doses greater than 107 bacteria. Until recently, these virulent strains were mostly antibiotic-susceptible. However, multidrug-resistant (MDR) hvKp strains have been emerging, spawning a new generation of hypervirulent “superbugs.” The mechanisms of hypervirulence are not fully defined, but overproduction of capsular polysaccharide significantly impedes host clearance, resulting in increased pathogenicity of hvKp strains. While there are more than 80 serotypes of K. pneumoniae, the K1 and K2 serotypes cause the vast majority of hypervirulent infections. Therefore, a glycoconjugate vaccine targeting these 2 serotypes could significantly reduce hvKp infection. Conventionally, glycoconjugate vaccines are manufactured using intricate chemical methodologies to covalently attach purified polysaccharides to carrier proteins, which is widely considered to be technically challenging. Here we report on the recombinant production and analytical characterization of bioconjugate vaccines, enzymatically produced in glycoengineered Escherichia coli cells, against the 2 predominant hypervirulent K. pneumoniae serotypes, K1 and K2. The K. pneumoniae bioconjugates are immunogenic and efficacious, protecting mice against lethal infection from 2 hvKp strains, NTUH K-2044 and ATCC 43816. This preclinical study constitutes a key step toward preventing further global dissemination of hypervirulent MDR hvKp strains.
Klebsiella pneumoniae, vaccine, glycoconjugate, bioconjugation, hypervirulent
Structure type: polymer chemical repeating unit
Location inside paper: p.18657, fig.2D-F, K2
Trivial name: K-antigen
Compound class: CPS, O-polysaccharide
Contained glycoepitopes: IEDB_115136,IEDB_1334432,IEDB_1334433,IEDB_1334434,IEDB_1334435,IEDB_137485,IEDB_140630,IEDB_142488,IEDB_144983,IEDB_144998,IEDB_146664,IEDB_152206,IEDB_153755,IEDB_983930,IEDB_983931,SB_192,SB_44,SB_72
Methods: 13C NMR, 1H NMR, NMR-2D, DNA techniques, ELISA, Western blotting, genetic methods, conjugation, glycoengineering, murine vaccination
Related record ID(s): 664, 665, 989
NCBI Taxonomy refs (TaxIDs): 573,
562Reference(s) to other database(s): GTC:G73682RA, GlycomeDB:
2875
Show glycosyltransferases
NMR conditions: in D2O at 308 K
[as TSV]
13C NMR data:
Linkage Residue C1 C2 C3 C4 C5 C6
4,4 bDGlcp 103.6 73.5 83.8 71.5 77.5 62.2
4,3 aDGlcpA 102.7 72.8 74.5 72.5 72.8 180.3
4 bDManp 101.0 72.1 82.4 73.4 76.7 61.1
aDGlcp 100.3 73.5 72.7 79.9 71.5 61.0
1H NMR data:
Linkage Residue H1 H2 H3 H4 H5 H6
4,4 bDGlcp 4.54 3.38 3.64 3.54 3.54 3.74-3.98
4,3 aDGlcpA 5.22 3.57 3.82 3.60 4.34 -
4 bDManp 4.78 4.21 3.88 4.08 3.59 3.84-4.01
aDGlcp 5.30 3.38 3.89 3.70 4.07 3.75-3.80
1H/13C HSQC data:
Linkage Residue C1/H1 C2/H2 C3/H3 C4/H4 C5/H5 C6/H6
4,4 bDGlcp 103.6/4.54 73.5/3.38 83.8/3.64 71.5/3.54 77.5/3.54 62.2/3.74-3.98
4,3 aDGlcpA 102.7/5.22 72.8/3.57 74.5/3.82 72.5/3.60 72.8/4.34
4 bDManp 101.0/4.78 72.1/4.21 82.4/3.88 73.4/4.08 76.7/3.59 61.1/3.84-4.01
aDGlcp 100.3/5.30 73.5/3.38 72.7/3.89 79.9/3.70 71.5/4.07 61.0/3.75-3.80
1H NMR data:
| Linkage | Residue | H1 | H2 | H3 | H4 | H5 | H6 |
|---|
| 4,4 | bDGlcp | 4.54 | 3.38 | 3.64 | 3.54 | 3.54 | 3.74
3.98 |
| 4,3 | aDGlcpA | 5.22 | 3.57 | 3.82 | 3.60 | 4.34 |
|
| 4 | bDManp | 4.78 | 4.21 | 3.88 | 4.08 | 3.59 | 3.84
4.01 |
| | aDGlcp | 5.30 | 3.38 | 3.89 | 3.70 | 4.07 | 3.75
3.80 |
|
13C NMR data:
| Linkage | Residue | C1 | C2 | C3 | C4 | C5 | C6 |
|---|
| 4,4 | bDGlcp | 103.6 | 73.5 | 83.8 | 71.5 | 77.5 | 62.2 |
| 4,3 | aDGlcpA | 102.7 | 72.8 | 74.5 | 72.5 | 72.8 | 180.3 |
| 4 | bDManp | 101.0 | 72.1 | 82.4 | 73.4 | 76.7 | 61.1 |
| | aDGlcp | 100.3 | 73.5 | 72.7 | 79.9 | 71.5 | 61.0 |
|
There is only one chemically distinct structure:
report error
Found 1 record.
Displayed record 1
