Function-specific epistasis shapes evolutionary trajectories towards antibiotic resistance

Area of Science:

• Evolutionary Biology
• Microbiology
• Genetics

Background:

• Pre-existing mutations influence evolution via epistasis.
• Global epistasis can predict evolutionary paths, but idiosyncratic epistasis introduces unpredictability.

Purpose of the Study:

• To investigate the predictability of antibiotic resistance evolution across diverse genetic backgrounds.
• To elucidate the role of function-specific epistasis in modulating resistance trajectories.

Main Methods:

• Utilized robotic evolution experiments to quantitatively analyze resistance trajectories.
• Examined three antibiotics across hundreds of Escherichia coli gene-deletion strains and clinical isolates.
• Identified genetic changes associated with alternative evolutionary paths.

Main Results:

• Antibiotic resistance evolution is largely repeatable but shows deviations in a subset of genetic backgrounds.
• Function-specific epistasis, not global epistasis, explains these deviations.
• Disrupting specific cellular functions alters drug resistance evolution, often slowing it down.

Conclusions:

• Function-specific epistasis creates novel, less predictable evolutionary trajectories for antibiotic resistance.
• These findings suggest that targeting specific cellular functions could be a strategy to combat resistance.
• Exploiting function-specific epistasis may offer new therapeutic approaches to improve antibiotic treatments.