# Heterogeneous multicopy of blaCTX-M variants on the same plasmid enhances evolutionary adaptability in clinical Klebsiella pneumoniae

## TL;DR

Bacteria can better survive antibiotics by having multiple copies of resistance genes on a single plasmid, which helps them adapt to changing drug pressures.

## Contribution

The study reveals that heterogeneous multicopy blaCTX-M variants on a single plasmid enhance bacterial adaptability under fluctuating antibiotic pressures.

## Key findings

- A Klebsiella pneumoniae isolate resistant to ceftazidime/avibactam has heterogeneous multicopy blaCTX-M genes on a single plasmid.
- Heterogeneous multicopy blaCTX-M variants on one plasmid provide greater stability and competitive advantage than separate plasmids during drug switching.
- Re-analysis of genomic datasets supports the universality of this evolutionary strategy in clinical settings.

## Abstract

Pathogenic bacteria continually evolve under antimicrobial pressure through acquired resistance genes, making it crucial to understand their evolutionary strategies. We identify a clinical Klebsiella pneumoniae isolate resistant to ceftazidime/avibactam (CZA), harboring heterogeneous multicopy blaCTX-M, among which a blaCTX-M-249 variant mediates CZA resistance. Both blaCTX-M-249 and its closely related allele blaCTX-M-65 are dominant within the clonal population and are located at two loci on the same plasmid, with their proportions shifting under antibiotic pressure. Using experimental and mathematical models, we demonstrate that the heterogeneous arrangement of blaCTX-M variants on the same plasmid confers greater stability and competitive advantage than that across separate plasmids, particularly during drug switching. Re-analysis of large genomic datasets supports the universality of this phenomenon. Our findings reveal an evolutionary strategy in which β-lactamase genes, through multicopy heterogeneity on a single plasmid, ensure stable inheritance of resistance and enhance bacterial adaptability under fluctuating clinical antibiotic pressures.

In this study, authors reveal an evolutionary strategy in bacteria, where multidrug resistance are stably maintained through multicopy heterogeneous genes on a single plasmid, conferring an adaptive advantage under fluctuating clinical drug pressures.