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

doi:10.1021/acsinfecdis.0c00661

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

ACS Infect Dis. 2021 Jun 11;7(6):1584-1595. doi: 10.1021/acsinfecdis.0c00661. Epub 2021 Apr 9.

Authors

Nusaibah Abdul Rahim^{1

2}, Yan Zhu², Soon-Ee Cheah¹, Matthew D Johnson², Heidi H Yu², Hanna E Sidjabat³, Mark S Butler⁴, Matthew A Cooper⁴, Jing Fu⁵, David L Paterson^{3

6}, Roger L Nation¹, John D Boyce², Darren J Creek¹, Phillip J Bergen^{2

7}, Tony Velkov⁸, Jian Li^{1

2}

Affiliations

¹ Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052, Australia.
² Biomedicine Discovery Institute, Department of Microbiology, Monash University, Clayton, Victoria 3800, Australia.
³ University of Queensland Centre for Clinical Research, Herston, Queensland 4029, Australia.
⁴ Institute for Molecular Biosciences, The University of Queensland, Brisbane, Queensland 4072, Australia.
⁵ Department of Mechanical and Aerospace Engineering, Faculty of Engineering, Monash University, Clayton, Victoria 3800, Australia.
⁶ Pathology Queensland, Royal Brisbane and Women's Hospital Campus, Herston, Queensland 4029, Australia.
⁷ Centre for Medicine Use and Safety, Monash University, Parkville, Victoria 3052, Australia.
⁸ Department of Pharmacology & Therapeutics, Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Parkville, Victoria 3010, Australia.

PMID: 33834753
DOI: 10.1021/acsinfecdis.0c00661

Abstract

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.

Keywords: Klebsiella pneumoniae; New Delhi metallo-β-lactamase; combination therapy; polymyxin; systems pharmacology.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Chloramphenicol / pharmacology
Drug Resistance, Multiple, Bacterial
Humans
Klebsiella Infections*
Klebsiella pneumoniae* / genetics
Microbial Sensitivity Tests
Polymyxins
United States
beta-Lactamases

Substances

Polymyxins
Chloramphenicol
beta-Lactamases
beta-lactamase NDM-1

Grants and funding

R01 AI111965/AI/NIAID NIH HHS/United States