Biophysical Society Thematic Meeting | Stockholm 2022

Physical and Quantitative Approaches to Overcome Antibiotic Resistance

Wednesday Speaker Abstracts

IMPROVING SMALL-MOLECULE UPTAKE USING SIMULATIONS AND DATA Peter Kasson University of Virginia, USA No Abstract

EVALUATING THE INTERACTION BETWEEN COPPER RESISTANT AND ANTIBIOTIC RESISTANT E. COLI Sada Boyd University of California, Los Angeles No Abstract

NONGENETIC RESISTANCE ENHANCES POPULATION SURVIVAL WHILE HINDERING THE EVOLUTION OF DRUG RESISTANCE

Joshua Guthrie 1 ; Harold Flohr 1 ; Daniel Charlebois 1,2 ; 1 University of Alberta, Physics, Edmonton, AB, Canada 2 University of Alberta, Biological Sciences, Edmonton, AB, Canada

Rising rates of resistance to antimicrobial drugs threatens the effective treatment of infections across the globe. Drug resistance has been established to emerge from nongenetic mechanisms, such as "persistence" in quiescent microbes and fluctuations or “noise” in gene expression in actively replicating cells, as well as from genetic mutations. However, it is still unclear how nongenetic drug resistance affects the evolution of genetic drug resistance. Using deterministic and stochastic population models that incorporate nongenetic and genetic forms of drug resistance, as well as resource competition between these subpopulations, we find that nongenetic resistance can enhance survival while at the same time hinder the evolution of genetic resistance. Nongenetic resistance in the presence of subpopulation competition is found to increase the fixation time of drug resistance mutations, while increasing the probability of mutation before population extinction during drug exposure. Intense intraspecific competition during drug treatment leads to extinction of susceptible and nongenetically resistant subpopulations. We are presently experimentally investigating these findings using genetically engineered budding yeast (Saccharomyces cerevisiae) that carry synthetic gene circuits to control drug resistance genes. These well-characterized synthetic gene circuits enable the precise control of gene expression mean and noise levels during drug resistance evolution experiments. Overall, these findings are advancing our understanding of antimicrobial resistance and leading to new therapeutic strategies to improve the outcome for patients with drug-resistant infections.

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