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 HuangJoelle El HamoucheGuiqing WangMelissa SmithChanghong YinAbhay DhandNevenka DimitrovaJohn T FallonPublished in: International journal of molecular sciences (2020)
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.
Keyphrases
- antimicrobial resistance
- gram negative
- multidrug resistant
- genome wide
- dna methylation
- acinetobacter baumannii
- transcription factor
- copy number
- pseudomonas aeruginosa
- drug resistant
- klebsiella pneumoniae
- genome wide analysis
- genome wide identification
- gene expression
- cystic fibrosis
- single cell
- poor prognosis
- high glucose
- biofilm formation
- dna binding
- case report
- diabetic rats
- endothelial cells
- protein protein
- mass spectrometry
- escherichia coli
- genetic diversity