Stochastic Gene Expression Influences the Selection of Antibiotic Resistance Mutations.

Bacteria can resist antibiotics by expressing enzymes that remove or deactivate drug molecules. Here, we study the effects of gene expression stochasticity on efflux and enzymatic resistance. We construct an agent-based model that stochastically simulates multiple biochemical processes in the cell and we observe the growth and survival dynamics of the cell population. Resistance-enhancing mutations are introduced by varying parameters that control the enzyme expression or efficacy. We find that stochastic gene expression can cause complex dynamics in terms of survival and extinction for these mutants. Regulatory mutations, which augment the frequency and duration of resistance gene transcription, can provide limited resistance by increasing mean expression. Structural mutations, which modify the enzyme or efflux efficacy, provide most resistance by improving the binding affinity of the resistance protein to the antibiotic; increasing the enzyme's catalytic rate alone may contribute to resistance if drug binding is not rate limiting. Overall, we identify conditions where regulatory mutations are selected over structural mutations, and vice versa. Our findings show that stochastic gene expression is a key factor underlying efflux and enzymatic resistances and should be taken into consideration in future antibiotic research.