Author ORCID Identifier
https://orcid.org/0000-0002-3229-2787
Date of Award
Spring 4-21-2025
Document Type
Thesis (Ph.D.)
Department or Program
Quantitative Biomedical Sciences
First Advisor
Daniel Schultz
Abstract
Bacterial populations exposed to antibiotics often exhibit phenotypic heterogeneity, with individual cells displaying distinct responses with fates ranging from survival to arrest or death. The emergence of this heterogeneity is largely driven by feedback mechanisms mediated by the interactions between antibiotic action, gene regulation, and cellular metabolism. These responses unfold in dynamic environments where conditions such as nutrient availability and drug concentration fluctuate over time and space. Yet, these complex interactions and their role in shaping population-level outcomes during drug responses remain poorly understood. Using tetracycline resistance in E. coli as a model system, this thesis focuses on how these interconnected processes integrate with environmental factors to drive bacterial survival in the context of dynamical responses to antibiotic exposure. Using single-cell and biofilm microfluidics, mathematical modeling, and RNA sequencing, we describe the mechanisms by which tetracycline exposure induces the emergence of heterogeneous phenotypes. We also show that in spatially structured populations, nutrient gradients lead to the emergence of a range of metabolic states that mediate a collective mechanism of survival to drug exposures. Finally, we describe how selective pressures relating to the costs and benefits of expressing resistance shape the evolution of the regulation of drug responses. These findings provide a quantitative framework to understand how bacteria survive antibiotic exposure and adapt to changing environments. By quantitatively linking gene regulation, metabolism, and antibiotic response dynamics, this thesis provides insights into bacterial adaptation under antibiotic stress, aiding the design of antibiotic therapies that minimize population-level resistance.
Original Citation
Stevanovic M, Carvalho J P T, Bittihn P, and Schultz D 2024 Dynamical model of antibiotic responses linking expression of resistance genes to metabolism explains emergence of heterogeneity during drug exposures Phys. Biol. 21 036002
Stevanovic M, Boukéké-Lesplulier T, Hupe L, Hasty J, Bittihn P and Schultz D 2022 Nutrient Gradients Mediate Complex Colony-Level Antibiotic Responses in Structured Microbial Populations Front. Microbiol. 13 740259
Schultz D, Stevanovic M, and Tsimring L S 2022 Optimal transcriptional regulation of dynamic bacterial responses to sudden drug exposures Biophys. J. 121 4137-4152
Recommended Citation
Stevanovic, Mirjana, "Emergence of Heterogeneity in Bacteria During Antibiotic Exposures" (2025). Dartmouth College Ph.D Dissertations. 399.
https://digitalcommons.dartmouth.edu/dissertations/399
