Synergy of the Polymyxin-Chloramphenicol Combination against New Delhi Metallo-β-Lactamase-Producing Klebsiella pneumoniae Is Predominately Driven by Chloramphenicol

Nusaibah Abdul Rahim, Yan Zhu, Soon-Ee Cheah, Matthew D. Johnson, Heidi H. Yu, Hanna E. Sidjabat, Mark S. Butler, Matthew A. Cooper, Jing Fu, David L. Paterson, Roger L. Nation, John D. Boyce, Darren J. Creek, Phillip J. Bergen, Tony Velkov, Jian Li

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3 Citations (Scopus)


Carbapenem-resistant Klebsiella pneumoniae has been classified as an Urgent Threat by the Centers for Disease Control and Prevention (CDC). The combination of two "old" antibiotics, polymyxin and chloramphenicol, displays synergistic killing against New Delhi metallo-β-lactamase (NDM)-producing K. pneumoniae. However, the mechanism(s) underpinning their synergistic killing are not well studied. We employed an in vitro pharmacokinetic/pharmacodynamic model to mimic the pharmacokinetics of the antibiotics in patients and examined bacterial killing against NDM-producing K. pneumoniae using a metabolomic approach. Metabolomic analysis was integrated with an isolate-specific genome-scale metabolic network (GSMN). Our results show that metabolic responses to polymyxin B and/or chloramphenicol against NDM-producing K. pneumoniae involved the inhibition of cell envelope biogenesis, metabolism of arginine and nucleotides, glycolysis, and pentose phosphate pathways. Our metabolomic and GSMN modeling results highlight the novel mechanisms of a synergistic antibiotic combination at the network level and may have a significant potential in developing precision antimicrobial chemotherapy in patients.

Original languageEnglish
Pages (from-to)1584–1595
Number of pages12
JournalACS Infectious Diseases
Issue number6
Publication statusPublished - 11 Jun 2021


  • combination therapy
  • Klebsiella pneumoniae
  • New Delhi metallo-β-lactamase
  • polymyxin
  • systems pharmacology

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