Evolution under vancomycin selection drives divergent collateral sensitivity patterns in Staphylococcus aureus.

Area of Science:

• Microbiology
• Genomics
• Evolutionary Biology

Background:

• Staphylococcus aureus bacteremia is often treated empirically with vancomycin.
• Current susceptibility testing does not account for adaptive changes during empiric treatment.
• Antimicrobial resistance development is a critical clinical challenge.

Purpose of the Study:

• To investigate collateral drug responses in Staphylococcus aureus during adaptation to vancomycin.
• To identify genetic pathways driving vancomycin resistance and associated collateral effects.
• To develop a quantitative measure for predicting these evolutionary responses.

Main Methods:

• Experimental evolution of 18 methicillin-susceptible S. aureus (MSSA) populations under increasing vancomycin concentrations.
• Genomic sequencing to identify mutations associated with vancomycin resistance.
• Analysis of collateral sensitivity profiles to various first-line antibiotics.
• Development of a Collateral Response Score (CRS) to quantify adaptive responses.

Main Results:

• Two distinct adaptive pathways emerged, involving mutations in the WalKR regulon or rpsU.
• These pathways led to intermediate vancomycin resistance.
• Identified divergent collateral sensitivity profiles to other antibiotics based on the adaptive pathway.
• The Collateral Response Score effectively quantified the probability and magnitude of these responses.

Conclusions:

• Bacterial evolutionary dynamics significantly impact antimicrobial resistance outcomes.
• Rapid genomic diagnostics combined with susceptibility testing can improve antimicrobial therapy.
• A probabilistic approach to treatment, informed by evolutionary insights, is recommended.
• Understanding adaptive pathways is crucial for anticipating and managing treatment responses.