Down the Resistance Road: An Exploration of the Evolution and Emergence of Antibiotic Resistance in Enterococcus faecalis Communities
Abstract
Antibiotic resistance poses a growing and global threat to public health. The rapid resistance evolution of microbes challenges our ability to control infections and leads to increased mortality. In this work, we explore the dynamics of antibiotic resistance evolution and the emergence of cooperative resistance---a phenomenon where antibiotic susceptible cells survive in drug environments due to cooperative interactions with antibiotic resistant cells---through a combination of experimental assays and mathematical modeling. To examine these dynamics, we use Enterococcus faecalis, a common pathogen in hospital-acquired infections that is notorious for its capacity to acquire resistance and to remain viable in biofilms. In the first study, we use a continuous culture bioreactor to subject an isogenic bacterial population to a combination of linezolid and levofloxacin to explore the effects of antagonistic antibiotics (i.e., ones that work less effectively in combination as opposed to synergistic combinations, where the efficacy of the drug is enhanced by the presence of the other) on the rate of resistance evolution. Our results show how this pair can inhibit evolutionary resistance, challenging conventional therapies favoring synergistic combinations. In the second study, we present a fluorescent-reporter library tailored to E. faecalis that facilitates following the single-cell level dynamics of populations in spatially fixed systems and in bulk assays. Lastly, we apply this…
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