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.
Highlights
Pseudomonas aeruginosa is one of the leading causes of nosocomial infections with an estimated 32,600 healthcare-associated infections and 2700 deaths per year in the United States [1]
PB367 was resistant to P/T with a higher minimum inhibitory concentration (MIC), but susceptible to both CZA and C/T
Integrated profiling of genome, epigenome, and transcriptome provides a global and comprehensive view for functional study. We adopted it to analyze an isogenic pair of P. aeruginosa clinical isolates with differential antimicrobial resistance, and found certain advantages
Summary
Pseudomonas aeruginosa is one of the leading causes of nosocomial infections with an estimated 32,600 healthcare-associated infections and 2700 deaths per year in the United States [1]. MDR P. aeruginosa is, categorized as a serious threat to public health by the Centers for Disease Control and Prevention (CDC) [1]. Characterizing P. aeruginosa clinical lineages and determining how they adapt and acquire multiple antimicrobial resistance elements are, of high scientific and clinical importance. The repertoire of P. aeruginosa genes, foundational to respond and adapt to diverse environments, are substantially conserved with a high proportion of regulatory genes and networks observed in other known bacterial genomes [3,4,5,6]. P. aeruginosa genome often carries many diverse mobile genetic elements responsible for horizontal gene transfer, which include plasmids, prophages, integrative and conjugative elements, insertion sequences, and transposons
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