Combating Cooperative Antibiotic Resistance

Combating Cooperative Antibiotic Resistance

Antibiotic resistance is a significant public health concern, causing more than 2 million illnesses and 23,000 deaths each year. To better combat the problem of antibiotic resistance, we studied the effects of cheater bacteria using a strain of Escherichia coli with the ability to express β-lactamase. Specifically, we mapped the conditions that cause cooperative bacteria to exhibit a strong Allee effect – in which colony survival depends on the initial population exceeding a certain minimum threshold. Bacteria that express β-lactamase confer protection to the population when ampicillin is present. This provides an incentive for cheater bacteria to enjoy the benefits of the enzyme without paying the metabolic costs of production. Using an intraspecific competitive Lotka-Volterra model along with experimental data, we studied the growth of normal (“cheater”) and resistant (“cooperator”) bacteria under various initial conditions of population, fraction resistant, and antibiotic concentration. The strongly nonlinear nature of the equations leads to a pronounced Allee effect within a certain range of antibiotic concentrations. The final population density as a function of the initial population becomes increasingly sigmoidal in shape as the level of cooperativity increases, measured using a modified Hill function. At the extremes, a population of all cooperators shows a “all-or-nothing” survival curve characteristic of the Allee effect, while an experiment with only cheaters (“every bacterium for itself”) has a much more linear response. Cooperativity is strongest with a small initial population of pure cooperators. The threshold dose required to eradicate the infection may be reduced by the purposeful introduction of cheater strains. The results of this study may inform efforts to design antibiotic treatment regimens that minimize the risk of resistance.