Synergy of the Polymyxin-Chloramphenicol Combination against New Delhi Metallo-β-Lactamase-Producing Klebsiella pneumoniae Is Predominately Driven by Chloramphenicol
| Autor: | Yan Zhu, Nusaibah Abdul Rahim, Matthew D. Johnson, Hanna E. Sidjabat, David L. Paterson, John D. Boyce, Phillip J. Bergen, Roger L. Nation, Mark E. Cooper, Mark S. Butler, Jing Fu, Darren J. Creek, Soon-Ee Cheah, Heidi H. Yu, Jian Li, Tony Velkov |
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| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
biology medicine.drug_class Klebsiella pneumoniae Chloramphenicol Polymyxin 030106 microbiology Antibiotics Drug resistance biology.organism_classification Microbiology 03 medical and health sciences 030104 developmental biology Infectious Diseases Antimicrobial chemotherapy medicine Rifampicin Polymyxin B medicine.drug |
| Zdroj: | ACS Infectious Diseases. 7:1584-1595 |
| ISSN: | 2373-8227 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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