Combating drug resistance with evolutionary biology

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Human pathogens that have evolved antimicrobial resistance are a daunting threat to human health. To tackle antimicrobial resistance, the therapeutic use of antimicrobial drugs is currently moving towards so-called adaptive therapies, which advocate minimized and more precise use of antimicrobials to minimize the risk of resistance evolution. To help develop adaptive therapies, our work employs laboratory evolution experiments aimed at devising new strategies to combat antimicrobial resistance. Our experimental system involves miniature bioreactors (1 mL) that support the continuous growth of pathogenic bacteria in a controlled and reproducible environment. Using these reactors, I study how pathogens evolve resistance in real-time by monitoring their growth rates, sequencing their genomes, and measuring the impact of antibiotic-resistance mutations on biological molecules. I use this accurate, quantitative information to helps us better understand how antibiotic resistance evolves and the roles of genetic and environmental factors, and how unique vulnerabilities of resistant pathogens can be used to combat these pathogens or force them to lose resistance. This project will provide a quantitative understanding of how the human pathogen Staphylococcus aureus evolves resistance to the antibiotic linezolid, which is commonly used against multi-drug resistant bacteria. I will assess the molecular defects of linezolid-resistant S. aureus cells, exposing evolutionary vulnerabilities that could be used to combat these resistant pathogens. Overall, this research can help devise new strategies to attenuate, prevent or reverse the evolution of antimicrobial resistance.