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
Tazobactam
RNA sequencing (RNAseq)
Microbial Sensitivity Tests
whole-genome sequencing (WGS)
Ceftazidime
piperacillin/tazobactam (P/T)
Article
03 medical and health sciences
Drug Resistance, Bacterial
Humans
Pseudomonas Infections
antimicrobial resistance
ceftazidime/avibactam (CZA)
Aged
Piperacillin
0303 health sciences
ceftolozane/tazobactam (C/T)
Anti-Bacterial Agents
Cephalosporins
3. Good health
<i>Pseudomonas aeruginosa</i>
Drug Combinations
Pseudomonas aeruginosa
Female
epigenetic profiling
Azabicyclo Compounds
Genome-Wide Association Study
DOI:
10.3390/ijms21031026
Publication Date:
2020-02-05T08:18:48Z
AUTHORS (8)
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.
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