Antibiotic interactions shape short-term evolution of resistance in Enterococcus faecalis

Antibiotic combinations are increasingly used to combat bacterial infections. Multidrug therapies are a particularly important treatment option for E. faecalis, an opportunistic pathogen that contributes to high-inoculum infections such as infective endocarditis. While numerous synergistic drug combinations for E. faecalis have been identified, much less is known about how different combinations impact the rate of resistance evolution. In this work, we use high-throughput laboratory evolution experiments to quantify adaptation in growth rate and drug resistance of E. faecalis exposed to drug combinations exhibiting different classes of interactions, ranging from synergistic to suppressive. We identify a wide range of evolutionary behavior, including both increased and decreased rates of growth adaptation, depending on the specific interplay between drug interaction and drug resistance profiles. For example, selection in a dual \textbeta-lactam combination leads to accelerated growth ada...