Integrated genome-wide analysis of an isogenic pair of pseudomonas aeruginosa clinical isolates with differential antimicrobial resistance to ceftolozane/tazobactam, ceftazidime/avibactam, and piperacillin/tazobactam

Weihua Huang, Joelle El Hamouche, Guiqing Wang, Melissa Smith, Changhong Yin, Abhay Dhand, Nevenka Dimitrova, John T. Fallon

Research output: Contribution to journalArticlepeer-review

9 Scopus citations

Abstract

Multidrug-resistant (MDR) Pseudomonas aeruginosa is one of the main causes of morbidity and mortality in hospitalized patients and the leading cause of nosocomial infections. We investigated, here, two MDR P. aeruginosa clinical isolates from a hospitalized patient with differential antimicrobial resistance to ceftazidime/avibactam (CZA), ceftolozane/tazobactam (C/T), and piperacillin/tazobactam (P/T). Their assembled complete genomes revealed they belonged to ST235, a widespread MDR clone; and were isogenic with only a single nucleotide variant, causing G183D mutation in AmpC β-lactamase, responsible for a phenotypic change from susceptible to resistant to CZA and C/T. Further epigenomic profiling uncovered two conserved DNA methylation motifs targeted by two distinct putative methyltransferase-containing restriction-modification systems, respectively; more intriguingly, there was a significant difference between the paired isolates in the pattern of genomic DNA methylation and modifications. Moreover, genome-wide gene expression profiling demonstrated the inheritable genomic methylation and modification induced 14 genes being differentially regulated, of which only toxR (downregulated), a regulatory transcription factor, had its promoter region differentially methylate and modified. Since highly expressed opdQ encodes an OprD porin family protein, therefore, we proposed an epigenetic regulation of opdQ expression pertinent to the phenotypic change of P. aeruginosa from resistant to susceptible to P/T. The disclosed epigenetic mechanism controlling phenotypic antimicrobial resistance deserves further experimental investigation.

Original languageEnglish
Article number1026
JournalInternational Journal of Molecular Sciences
Volume21
Issue number3
DOIs
StatePublished - 1 Feb 2020
Externally publishedYes

Keywords

  • Antimicrobial resistance
  • Ceftazidime/avibactam (CZA)
  • Ceftolozane/tazobactam (C/T)
  • Epigenetic profiling
  • Piperacillin/tazobactam (P/T)
  • Pseudomonas aeruginosa
  • RNA sequencing (RNAseq)
  • Whole-genome sequencing (WGS)

Fingerprint

Dive into the research topics of 'Integrated genome-wide analysis of an isogenic pair of pseudomonas aeruginosa clinical isolates with differential antimicrobial resistance to ceftolozane/tazobactam, ceftazidime/avibactam, and piperacillin/tazobactam'. Together they form a unique fingerprint.

Cite this