Β-lactamase Amplification and Porin Loss Drive Progressive β-lactam Resistance in Recurrent ESBL Enterobacteriaceae Bacteremia

William C. Shropshire, Samuel L. Aitken, Reed Pifer, Jiwoong Kim, Micah M. Bhatti, Xiqi Li, Awdhesh Kalia, Jessica Galloway-Peña, Pranoti Sahasrabhojane, Cesar A. Arias, David E. Greenberg, Blake M. Hanson, Samuel A. Shelburne

Research output: Contribution to journalArticlepeer-review

Abstract

Carbapenem resistant Enterobacteriaceae (CRE) are a critical public health issue. Recent studies indicate many CRE lack carbapenemases, but contain extended spectrum β-lactamases (ESBLs). We investigated 16 longitudinal, recurrent cases of extended spectrum B-lactamase (ESBL)-positive Enterobacteriaceae bacteremia to gain insights into mechanisms underlying the emergence of non-carbapenemase producing CRE (non-CP-CRE). Using a combination of short- and long-read sequencing technologies, we identified that non-CP-CRE emerges from an ESBL background through a combination of insertion sequence mediated β-lactamase translocation, subsequent amplification of β-lactamase encoding genes such as blaOXA-1 and blaCTX-M, and porin inactivation. Interestingly, the β-lactamase gene amplification occurred both on plasmids and on the chromosome, including in the middle of porin-encoding genes. Additionally, overexpression of blaOXA-1 increased resistance to the broad-spectrum β-lactam, piperacillin-tazobactam. This analysis shows mechanisms underlying non-CP-CRE emergence and demonstrates that copy number of β-lactamase genes needs to be considered to fully understand antimicrobial resistance amongst key human pathogens. One Sentence Summary Amplification of β-lactam genes with porin loss was associated with development of β-lactam resistance in serial Enterobacteriaceae clinical isolates.

Original languageEnglish (US)
JournalUnknown Journal
DOIs
StatePublished - Apr 23 2019

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • Immunology and Microbiology(all)
  • Neuroscience(all)
  • Pharmacology, Toxicology and Pharmaceutics(all)

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