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Peer-reviewedCC BY 4.0Microbiology Spectrum

PBT2 potentiates carbapenem antibiotics against diverse Klebsiella pneumoniae strains

  • Aimee Tan1
  • Abigail R. Hartono1
  • Adam P. Gunn1
  • Claire L. Gorrie1,2,3
  • David M. P. De Oliveira4
  • Francesca L. Short5
  • Mark J. Walker4
  • Norelle L. Sherry1,2,3,6
  • Benjamin P. Howden1,2,3,6,7
  • Christopher A. McDevitt1
7 affiliations
  1. 1Department of Microbiology and Immunology at the Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, Victoria, Australia
  2. 2Centre for Pathogen Genomics, University of Melbourne, Melbourne, Victoria, Australia
  3. 3Microbiological Diagnostic Unit (MDU) Public Health Laboratory, Department of Microbiology and Immunology at the Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, Victoria, Australia
  4. 4Centre for Superbug Solutions, Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland, Australia
  5. 5Department of Microbiology, Infection Program, Biomedicine Discovery Institute, Monash University, Clayton, Victoria, Australia
  6. 6Department of Infectious Diseases and Immunology, Austin Health, Heidelberg, Victoria, Australia
  7. 7Department of Microbiology, Royal Melbourne Hospital, Parkville, Victoria, Australia
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Abstract

Carbapenem-resistant Klebsiella pneumoniae is recognized by the World Health Organization as a critical priority for urgent antimicrobial development. Due to the lack of novel antimicrobial classes in the development pipeline, this study investigated the application of an antibiotic potentiator, the zinc ionophore PBT2, to restore the utility of critical antibiotics. The data show that zinc and PBT2 can increase the sensitivity of diverse clinical strains of K. pneumoniae to carbapenem antibiotics, including those strains containing metallo-β-lactamases and porin mutations. PBT2 induced zinc and iron dyshomeostasis in these strains, resulting in altered uptake of multiple antimicrobial agents. Furthermore, PBT2 exposure also decreased resistance to agents, including ethanol and hydrogen peroxide, and reduced the potential for horizontal gene mobilization. Collectively, these impacts on metal homeostasis and cell composition suggest that PBT2 may have potential as an adjunct therapy for the treatment of multidrug-resistant K. pneumoniae.IMPORTANCECarbapenem-resistant Klebsiella pneumoniae is a major nosocomial threat and a top World Health Organization priority for urgent antimicrobial development. Resistance can be mediated by multiple classes of mobilizable carbapenemase enzymes, with varied treatment recommendations, depending on which class is present. This work describes how a repurposed drug called PBT2 can potentiate carbapenem activity against a clinical K. pneumoniae panel, independent of resistance mechanism. This could support the development of PBT2 as a broad-spectrum potentiator compound against drug-resistant K. pneumoniae.

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Cite

BibTeXRIS
BibTeX
@article{tan2026pbt2,
  title = {{PBT2 potentiates carbapenem antibiotics against diverse Klebsiella pneumoniae strains}},
  author = {Aimee Tan and Abigail R. Hartono and Adam P. Gunn and Claire L. Gorrie and David M. P. De Oliveira and Francesca L. Short and Mark J. Walker and Norelle L. Sherry and Benjamin P. Howden and Christopher A. McDevitt},
  journal = {Microbiology Spectrum},
  year = {2026},
  month = sep,
  doi = {10.1128/spectrum.02109-26},
  url = {https://doi.org/10.1128/spectrum.02109-26},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - PBT2 potentiates carbapenem antibiotics against diverse Klebsiella pneumoniae strains
AU  - Aimee Tan
AU  - Abigail R. Hartono
AU  - Adam P. Gunn
AU  - Claire L. Gorrie
AU  - David M. P. De Oliveira
AU  - Francesca L. Short
AU  - Mark J. Walker
AU  - Norelle L. Sherry
AU  - Benjamin P. Howden
AU  - Christopher A. McDevitt
PY  - 2026
DA  - 2026/09/25
JO  - Microbiology Spectrum
DO  - 10.1128/spectrum.02109-26
UR  - https://doi.org/10.1128/spectrum.02109-26
AB  - Carbapenem-resistant Klebsiella pneumoniae is recognized by the World Health Organization as a critical priority for urgent antimicrobial development. Due to the lack of novel antimicrobial classes in the development pipeline, this study investigated the application of an antibiotic potentiator, the zinc ionophore PBT2, to restore the utility of critical antibiotics. The data show that zinc and PBT2 can increase the sensitivity of diverse clinical strains of K. pneumoniae to carbapenem antibiotics, including those strains containing metallo-β-lactamases and porin mutations. PBT2 induced zinc and iron dyshomeostasis in these strains, resulting in altered uptake of multiple antimicrobial agents. Furthermore, PBT2 exposure also decreased resistance to agents, including ethanol and hydrogen peroxide, and reduced the potential for horizontal gene mobilization. Collectively, these impacts on metal homeostasis and cell composition suggest that PBT2 may have potential as an adjunct therapy for the treatment of multidrug-resistant K. pneumoniae.IMPORTANCECarbapenem-resistant Klebsiella pneumoniae is a major nosocomial threat and a top World Health Organization priority for urgent antimicrobial development. Resistance can be mediated by multiple classes of mobilizable carbapenemase enzymes, with varied treatment recommendations, depending on which class is present. This work describes how a repurposed drug called PBT2 can potentiate carbapenem activity against a clinical K. pneumoniae panel, independent of resistance mechanism. This could support the development of PBT2 as a broad-spectrum potentiator compound against drug-resistant K. pneumoniae.
SN  - 2165-0497
ER  -