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<p>A clinical <i>Escherichia coli</i> isolate (CDC AR Isolate Bank #0118) was found to be resistant to all beta-lactam antibiotics, including DOR, IPM, MER, and ERT, aztreonam-avibactam excluded. Genes associated with these resistance traits included <i>bla</i><sub>NDM-1</sub>, <i>bla</i><sub>CMY-6</sub>, <i>bla</i><sub>OXA-2</sub>, <i>bla</i><sub>TEM-1A</sub>, and <i>OmpF</i>. Isolate 0118 was subjected to continual antibiotic-free broth culture for 294&#xa0;days, with approximately 1 × 10<sup>7</sup> colony-forming units transferred at 24-h intervals. Following a 64-fold reduction in DOR resistance by day 287, a sub-inhibitory concentration of DOR was introduced during days 294–360 to introduce selective pressure. During this interval, DOR resistance increased approximately 250-fold, exceeding the initial level observed. Concurrently, loss of the plasmid-borne <i>bla</i><sub>NDM-1</sub> gene was detected by Day 140. <i>bla</i><sub>CMY-6</sub> was lost by day 319, while <i>bla</i><sub>OXA-2</sub> and <i>bla</i><sub>TEM-1A</sub> remained. Following growth in sub-inhibitory DOR levels, changes in MICs to non-beta-lactam antibiotics were also observed, and will be the subject of future investigations. Whole-genome sequencing identified structural mutations and large genomic deletions that coincided with these phenotypic changes, including loss of envelope- and stress-associated genes (<i>nlpD</i>, <i>rpoS</i>, <i>mutS</i>) and truncations in genes involved in membrane and peptidoglycan biosynthesis (murein transglycosylase; UDP-galactose LPS α1,2-galactosyltransferase). RNAseq analysis revealed convergent transcriptomic signatures including downregulation of DNA repair genes <i>mutS</i> and <i>mutY</i>, and repression of the global regulator <i>csrA.</i> Differential gene expression of chromosomally encoded genes involved in outer membrane remodeling, efflux pump activation, and cell wall precursor restructuring was also found.</p>

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Loss and resurgence of multi-drug-resistance during laboratory evolution of a carbapenem-resistant isolate of Escherichia coli

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月8日

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  • Taalin R. Hoj,
  • Allison Brower,
  • Alexa Owens,
  • Kylie Webber,
  • Joel S. Griffitts,
  • Richard A. Robison

摘要

A clinical Escherichia coli isolate (CDC AR Isolate Bank #0118) was found to be resistant to all beta-lactam antibiotics, including DOR, IPM, MER, and ERT, aztreonam-avibactam excluded. Genes associated with these resistance traits included blaNDM-1, blaCMY-6, blaOXA-2, blaTEM-1A, and OmpF. Isolate 0118 was subjected to continual antibiotic-free broth culture for 294 days, with approximately 1 × 107 colony-forming units transferred at 24-h intervals. Following a 64-fold reduction in DOR resistance by day 287, a sub-inhibitory concentration of DOR was introduced during days 294–360 to introduce selective pressure. During this interval, DOR resistance increased approximately 250-fold, exceeding the initial level observed. Concurrently, loss of the plasmid-borne blaNDM-1 gene was detected by Day 140. blaCMY-6 was lost by day 319, while blaOXA-2 and blaTEM-1A remained. Following growth in sub-inhibitory DOR levels, changes in MICs to non-beta-lactam antibiotics were also observed, and will be the subject of future investigations. Whole-genome sequencing identified structural mutations and large genomic deletions that coincided with these phenotypic changes, including loss of envelope- and stress-associated genes (nlpD, rpoS, mutS) and truncations in genes involved in membrane and peptidoglycan biosynthesis (murein transglycosylase; UDP-galactose LPS α1,2-galactosyltransferase). RNAseq analysis revealed convergent transcriptomic signatures including downregulation of DNA repair genes mutS and mutY, and repression of the global regulator csrA. Differential gene expression of chromosomally encoded genes involved in outer membrane remodeling, efflux pump activation, and cell wall precursor restructuring was also found.