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Nanomechanics of Drug-target Interactions and Antibacterial Resistance Detection
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Evolution under vancomycin selection drives divergent collateral sensitivity patterns in Staphylococcus aureus.

Dena Crozier1, Jason M Gray2,3, Jeff A Maltas1

  • 1Department of Translational Hematology & Oncology Research, Cleveland Clinic Lerner Research Institute, Cleveland, OH 44106.

Biorxiv : the Preprint Server for Biology
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Antibiotic resistance in Staphylococcus aureus evolves over time. This study shows vancomycin treatment can lead to resistance, impacting other antibiotics and suggesting penicillin-based drugs may be better initial choices for MSSA infections.

Keywords:
Biological SciencesEvolutionS. aureusantibiotic resistancecollateral sensitivityexperimental evolutionparallel evolution

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Area of Science:

  • Microbiology
  • Evolutionary Biology
  • Infectious Diseases

Background:

  • Staphylococcus aureus infections are serious and often treated empirically with vancomycin.
  • Current susceptibility testing may not predict drug efficacy during evolving infections.
  • Antibiotic resistance development is a significant clinical challenge.

Purpose of the Study:

  • To investigate how Staphylococcus aureus antibiotic susceptibility changes during vancomycin treatment.
  • To understand the evolutionary mechanisms driving resistance.
  • To inform therapeutic strategies by accounting for evolutionary dynamics.

Main Methods:

  • Evolved methicillin-susceptible S. aureus (MSSA) populations under increasing vancomycin concentrations.
  • Analyzed genetic mutations using sequencing.
  • Assessed cross-resistance to other antibiotics (daptomycin, meropenem, gentamicin, nafcillin).
  • Developed probabilistic models for drug response likelihood.

Main Results:

  • Parallel mutations affecting cell membrane and cell wall were observed.
  • Populations developed cross-resistance to daptomycin and varied responses to other antibiotics.
  • Evolutionary trajectories introduced uncertainty in predicting treatment outcomes.
  • Probabilistic likelihood estimates were derived to quantify drug response variability.

Conclusions:

  • Vancomycin treatment can induce resistance and alter susceptibility to other drugs in S. aureus.
  • Antistaphylococcal penicillins may be preferable first-line treatments for MSSA.
  • Therapeutic choices should consider the probabilistic nature of bacterial evolution during infection.