Combating drug resistance with evolutionary biology

已经进化出抗菌素耐药性的人类病原体是对人类健康的巨大威胁。为了解决抗菌素耐药性问题，抗菌药物的治疗性使用目前正朝着所谓的适应性疗法发展，这种疗法提倡最大限度地减少和更精确地使用抗菌药物，以最大限度地减少耐药性演变的风险。为了帮助开发适应性疗法，我们的工作采用了实验室进化实验，旨在设计对抗抗菌素耐药性的新策略。我们的实验系统包括微型生物反应器（1 mL），可支持病原菌在受控和可重现的环境中持续生长。使用这些反应器，我研究病原体如何通过监测它们的生长速率，测序它们的基因组以及测量生物分子上的抗药性突变的影响来实时进化抗性。我使用这些准确的定量信息来帮助我们更好地了解抗生素耐药性如何演变以及遗传和环境因素的作用，以及如何利用耐药病原体的独特脆弱性来对抗这些病原体或迫使它们失去耐药性。该项目将定量了解人类病原体金黄色葡萄球菌如何对抗生素利奈唑胺产生耐药性，利奈唑胺通常用于对抗多重耐药细菌。我将评估利奈唑胺耐药链球菌的分子缺陷。金黄色葡萄球菌细胞，暴露出可用于对抗这些耐药病原体的进化弱点。总的来说，这项研究可以帮助设计新的策略来减弱，预防或逆转抗生素耐药性的演变。

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.