Gene expression tradeoffs determine bacterial survival and adaptation to antibiotic stress

Abstract

To optimize their fitness, cells face the crucial task of efficiently responding to various stresses. This ne- cessitates striking a balance between conserving resources for survival and allocating resources for growth and division. The fundamental principles governing these tradeoffs is an outstanding challenge in the physics of living systems. In this study, we introduce a coarse-grained theoretical framework for bacterial physiology that establishes a connection between the physiological state of cells and their survival outcomes in dynamic environments, particularly in the context of antibiotic exposure. Predicting bacterial survival responses to varying antibiotic doses proves challenging due to the profound influence of the physiological state on critical parameters, such as the Minimum Inhibitory Concentration (MIC) and killing rates, even within an isogenic cell population. Our proposed theoretical model bridges the gap by linking extracellular antibiotic concentration and nutrient quality to intracellular damage accumulation and gene expression. This framework allows us to predict and explain the control of cellular growth rate, death rate, MIC and survival fraction in a wide range of time-varying environments. Surprisingly, our model reveals that cell death is rarely due to antibiotic levels being above the maximum physiological limit, but instead survival is limited by the inability to alter gene expression sufficiently quickly to transition to a less susceptible physiological state. Moreover, bacteria tend to overexpress stress response genes at the expense of reduced growth, conferring greater protection against further antibiotic exposure. This strategy is in contrast to those employed in different nutrient environments, in which bacteria allocate resources to maximize growth rate. This highlights an important tradeoff between the cellular capacity for growth and the ability to survive antibiotic exposure.