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Gene Expression Tradeoffs Determine Bacterial Survival and Adaptation to Antibiotic Stress

Josiah C. Kratz1,2 and Shiladitya Banerjee3,*

  • 1Computational Biology Department, Carnegie Mellon University, Pittsburgh, Pennsylvania 15213, USA
  • 2Department of Biological Sciences, Carnegie Mellon University, Pittsburgh, Pennsylvania 15213, USA
  • 3Department of Physics, Carnegie Mellon University, Pittsburgh, Pennsylvania 15213, USA

  • *Corresponding author: shiladtb@andrew.cmu.edu
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PRX Life 2, 013010 – Published 29 February, 2024

DOI: https://doi.org/10.1103/PRXLife.2.013010

Abstract

To optimize their fitness, cells face the crucial task of efficiently responding to various stresses. This necessitates 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.

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PRX Life 2, 013010– Published 29 February, 2024
  • Received 17 October 2023
  • Accepted 24 January 2024
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Published by the American Physical Society under the terms of the Creative Commons Attribution 4.0 International license. Further distribution of this work must maintain attribution to the author(s) and the published article's title, journal citation, and DOI.

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