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The following is a summary of “Comprehensive Assessment of Initial Adaptation of ESBL Positive ST131 Escherichia coli to Carbapenem Exposure,” published in the November 2024 issue of Infectious Disease by Shropshire et al.
Researchers conducted a retrospective study investigating the early adaptive mechanisms of high-risk Escherichia coli lineages, like sequence type (ST) 131, in response to carbapenem exposure.
They measured carbapenem mutation frequency in various subclades of extended-spectrum β-lactamase (ESBL) positive ST131 clinical isolates using a fluctuation assay, followed by whole genome sequencing (WGS) for characterization. Genomic, transcriptomic, and porin analyses of the ST131 C2/H30Rx isolate (MB1860) were conducted under prolonged, increasing carbapenem exposure, utilizing 2 experimental evolutionary platforms to evaluate fast and slow adaptation.
The results showed that all 13 ESBL positive ST131 strains from a diverse cohort (n=184) exhibited detectable ertapenem (ETP) mutational frequencies, with a strong positive correlation between initial ESBL gene copy number and mutation frequency (r = 0.87, P-value <1e-5), WGS analysis revealed that initial ETP exposure caused significant increases in ESBL gene copy numbers or mutations in outer membrane porin (Omp) genes, even without ESBL gene amplification, showing subclade-specific patterns, MB1860 increased blaCTX-M-15 copy numbers in both experimental platforms through insertion sequence 26 (IS26)-mediated pseudocompound transposons (PCTns) following ETP exposure. The increased transcript levels of PCTn genes were consistently observed in both platforms. Stable mutations in Omp genes emerged only after prolonged carbapenem exposure, reflecting clinical findings.
Investigators concluded the ESBL gene amplification had a conserved early response to carbapenem exposure, especially in the high-risk ST131 C2/H30Rx subclade, suggesting that targeting the me mechanism could potentially mitigate carbapenem resistance development.
Source: academic.oup.com/jid/advance-article/doi/10.1093/infdis/jiae587/7909583
