Abstract
Despite widespread resistance to many important antibiotics, the factors that govern the emergence and prevalence of antibiotic-resistant bacteria are still unclear. When exposed to antibiotic gradients in soft agar plates measuring as little as 1.25 × 11 cm we found that Escherichia coli rapidly became resistant to representatives from every class of antibiotics active against Gram-negative bacteria. Evolution kinetics were independent of the frequency of spontaneous mutations that confer antibiotic resistance or antibiotic dose-response curves, and were only loosely correlated to maximal antibiotic concentrations. Instead, rapid evolution required unrealized mutations that could markedly decrease antibiotic susceptibility. When bacteria could not evolve through these “high-impact” mutations, populations frequently bottlenecked, reducing the number of cells from which mutants could arise and prolonging evolution times. This effect was independent of the antibiotic’s mechanism of action, and may affect the evolution of antibiotic resistance in clinical settings.
Highlights
Antibiotic resistance is one of the greatest threats to modern medicine
By controlling the quantity of agar and the slope of the plate, it’s possible to create smooth gradients of arbitrary composition[10,11]. We found that these gradients are stable at soft agar concentrations (0.2–0.75% agar w/v, Fig. 1), that allow bacteria to swim throughout the plate[12]
Our findings show that in soft agar gradients evolution kinetics are constrained by the potential for high-impact mutations
Summary
Antibiotic resistance is one of the greatest threats to modern medicine. Antibiotic-resistant organisms are thought to cause over 2,000,000 infections and 23,000 deaths in the United States each year[1]. Evolution rates appeared to be constrained by the limited availability of potential high-impact mutations, unrealized changes to the genome that could markedly increase antibiotic resistance.
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