Antibiotic interactions shape short-term evolution of resistance in E. faecalis

Area of Science:

• Microbiology
• Evolutionary Biology
• Pharmacology

Background:

• Antibiotic combinations are vital for treating infections caused by opportunistic pathogens like Enterococcus faecalis.
• While synergistic drug combinations are known, their impact on the rate of resistance evolution remains understudied.
• Enterococcus faecalis is a significant contributor to high-inoculum infections, including infective endocarditis.

Purpose of the Study:

• To quantify how different antibiotic combination interaction types (synergistic to suppressive) affect the evolution of growth rate and drug resistance in E. faecalis.
• To explore the relationship between drug interaction profiles and resistance evolution trajectories.

Main Methods:

• Utilized high-throughput laboratory evolution experiments to expose E. faecalis to various drug combinations.
• Quantified adaptation in both growth rate and drug resistance across different evolutionary conditions.
• Employed rescaling arguments and geometric transformations to analyze two-drug growth response surfaces.

Main Results:

• Observed diverse evolutionary behaviors, including accelerated or decreased growth adaptation, contingent on drug interaction and resistance profiles.
• Dual beta-lactam combinations accelerated growth adaptation with minimal changes in resistance profiles compared to individual drugs.
• Aminoglycoside and beta-lactam combinations showed decreased growth adaptation, with resistance profiles varying by drug concentration.

Conclusions:

• Drug interactions and resistance profiles present trade-offs during the evolution of multidrug resistance.
• Specific drug pairs targeting enterococci exhibit distinct evolutionary advantages and disadvantages.
• Simple rescaling arguments can explain key features of evolutionary trajectories under drug combinations.