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Nanomechanics of Drug-target Interactions and Antibacterial Resistance Detection
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Adaptive laboratory evolution and independent component analysis disentangle complex vancomycin adaptation

Anaëlle Fait1, Yara Seif2,3, Kasper Mikkelsen1

  • 1Department of Veterinary and Animal Sciences, University of Copenhagen, Frederiksberg, 1870 Denmark.

Proceedings of the National Academy of Sciences of the United States of America
|July 20, 2022
PubMed
Summary

Laboratory evolution of vancomycin-intermediate Staphylococcus aureus (VISA) revealed diverse mutations and gene expression changes. These adaptations impact antibiotic susceptibility and could influence clinical outcomes in MRSA infections.

Keywords:
adaptive laboratory evolutionantibiotic resistancetranscriptional regulationvirulence

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Area of Science:

  • Microbiology
  • Genetics
  • Molecular Biology

Background:

  • Methicillin-resistant Staphylococcus aureus (MRSA) infections are often treated with vancomycin.
  • Vancomycin-intermediate S. aureus (VISA) strains are linked to treatment failures.

Purpose of the Study:

  • To investigate the genetic and transcriptional changes in VISA strains.
  • To understand the adaptive pathways leading to vancomycin intermediate resistance.

Main Methods:

  • Laboratory evolution of 10 VISA strains from a common MRSA ancestor (USA300 JE2).
  • Phenotypic, mutational, and transcriptional profiling using functional and independent component analysis.
  • Analysis of mutations in known resistance genes and novel adaptive genes.

Main Results:

  • Divergent mutational landscapes with both known and novel resistance-associated mutations.
  • Mutations occurred in waves, affecting transcriptional regulators then membrane biosynthesis.
  • Strain-specific expression profiles, with sceD and lukG consistently altered.
  • Perturbation of virulence systems (φSa3, SaeR, T7SS) and significant variation in oxacillin susceptibility.
  • VraR regulon expression linked to cross-susceptibility, walK mutations to cross-resistance.

Conclusions:

  • Vancomycin adaptation involves diverse mutational and transcriptional pathways.
  • These adaptations can alter antibiotic susceptibility and potentially affect clinical outcomes.
  • Understanding these pathways is crucial for managing MRSA infections.