CAREER: Investigating the Roles of Spatial Heterogeneity and Collateral Sensitivity in Evolved Bacterial Resistance to Environmental Stressors

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1553028 Wood, Kevin B. Microbes such as bacteria and fungi have developed a wide range of molecular tools for surviving in toxic environments, and they evolve resistance to new stressors with remarkable speed. The rise of antibiotic-resistant microbes poses an urgent threat to public health, while bacteria resistant to disinfectants and other biocides present engineering challenges in numerous venues, ranging from wastewater treatment to biotechnology. Bacterial resistance has garnered significant scientific interest over the past several decades, leading to a relatively mature understanding of the molecular events underlying resistance in individual cells. However, relatively little is known about how these molecular events contribute to the large-scale behavior of bacteria communities, which are often comprised of heterogeneous mixtures of billions of cohabitating cells. Is the behavior of a collection of cells simply a sum of its molecular and cellular parts, or is it instead dominated by new phenomena that arise from the way those parts fit together? This project attempts to answer this question by combining quantitative experiments on bacterial populations with mathematical and computational models of bacterial communities. The goal is to understand the way cellular communities respond to toxic stimuli ranging from antiseptics to disinfectants and harsh chemicals in realistic environments that may change over time. The work will offer fundamental insights into the community-level behavior of microbial populations and complement the current molecular-level understanding of resistance and its evolution. On a practical level, it will contribute to new engineering strategies for controlling and optimizing microbial growth while enhancing secondary student engagement with science and engineering practices (SEP) in underrepresented rural communities.This CAREER proposal includes integrated research and education plans focused on the evolution of resistance in bacterial populations. The goal of the research is to combine quantitative experiments on microbial populations with stochastic models of bacterial evolution to understand systems-level mechanisms by which cellular communities develop resistance to environmental stresses. The work will leverage customized, computer-automated microbial culture devices and high-throughput DNA sequencing to investigate the evolution of resistance to a wide range of deleterious stimuli, ranging from biocides to osmotic stress, in realistic environments characterized by spatial heterogeneity and temporal fluctuations. More specifically, the project will explore the roles of population density and collateral sensitivity, which encompasses the trade-offs inherent in optimizing resistance for one environment, in modulating the rate of resistance evolution. The work will offer a quantitative, systems-level perspective to complement the current molecular-level understanding of resistance and its evolution. It will also lay the groundwork for new engineering strategies for controlling and optimizing microbial growth, with applications for biotechnology and public health, including the fight against antibiotic resistance.The educational component includes a multi-faceted approach to enhance secondary student engagement with science and engineering practices (SEP) in rural regions of Kentucky. The educational outreach is directly related to the proposed research on bacterial resistance and involves collaboration with a leading education expert at the University of Kentucky and partnerships with local educators through the Kentucky Valley Educational Cooperative (KVEC), a collection of educational groups serving schools in rural regions of eastern Kentucky. The project uses a combination of annual site visits to participating high schools, regular distance learning meetings with teachers, students and practicing scientists, and electronic and online tools inspired by the proposed research on antimicrobial resistance. The goal of the proposal is to engage students in SEP for systems-level analysis of biological systems, increase student awareness of careers at the interface of traditional disciplines, and improve specific skills and intuition for mathematical and computational modeling of complex systems.This CAREER award by the Biotechnology and Biochemical Engineering Program of the CBET Division is co-funded by the Systems and Synthetic Biology Program of the Division of Molecular and Cellular Biosciences and by the Integrative Ecological Physiology Program of the Division of Integrative Organismal Systems.