Transcriptomic responses of a New Delhi metallo-β-lactamase-producing Klebsiella pneumoniae isolate to the combination of polymyxin B and chloramphenicol

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

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3 Citations (Scopus)

Abstract

The combination of polymyxins and chloramphenicol possesses synergistic killing activity against New Delhi metallo-β-lactamase (NDM)-producing Klebsiella pneumoniae. This systems study examined the transcriptomic responses to the polymyxin/chloramphenicol combination in clinical NDM-producing K. pneumoniae isolate S01. Klebsiella pneumoniae S01 (initial inoculum ~108 CFU/mL) was treated with polymyxin B (1 mg/L, continuous infusion) or chloramphenicol [maximum concentration (Cmax) = 8 mg/L, half-life (t1/2) = 4 h], alone or in combination, using an in vitro pharmacokinetic/pharmacodynamic (PK/PD) model to mimic their pharmacokinetics in patients. Transcriptomic profiles of bacterial samples collected at 0, 0.25, 1, 4 and 24 h were examined using RNA sequencing (RNA-Seq). Chloramphenicol monotherapy significantly increased the expression of genes involved in ribosomal synthesis across the entire 24-h treatment, reflective of chloramphenicol-mediated inhibition of protein synthesis. The effect of polymyxin B was rapid and no major pathways were perturbed at later time points (4 h and 24 h). Combination treatment yielded the highest number of differentially expressed genes, including a large number observed following chloramphenicol monotherapy, in particular carbohydrate, nucleotide, amino acid and cell wall metabolism. Notably, chloramphenicol alone and in combination with polymyxin B significantly inhibited the expression of the arn operon that is responsible for lipid A modification and polymyxin resistance. These results indicate that the polymyxin/chloramphenicol combination displayed persistent transcriptomic responses over 24 h mainly on cell envelope synthesis and metabolism of carbohydrates, nucleotides and amino acids.

Original languageEnglish
Article number106061
Number of pages9
JournalInternational Journal of Antimicrobial Agents
Volume56
Issue number2
DOIs
Publication statusPublished - Aug 2020

Keywords

  • Chloramphenicol
  • Klebsiella pneumoniae
  • New Delhi metallo-β-lactamase
  • Polymyxin B
  • Systems pharmacology
  • Transcriptomics

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