Combating drug resistance with evolutionary biology

已经进化出抗菌素耐药性的人类病原体对人类健康构成了可怕的威胁。为解决抗微生物药物耐药性问题，抗微生物药物的治疗使用目前正朝着所谓的适应性疗法发展，即提倡尽量减少和更精确地使用抗微生物药物，以尽量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（1ml），支持病原菌在受控和可复制的环境中持续生长。利用这些反应器，我通过监测病原体的生长速度、测序它们的基因组和测量抗生素耐药性突变对生物分子的影响，来研究病原体如何实时进化耐药性。我利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是如何演变的，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进化出对抗生素利奈唑胺的耐药性，利奈唑胺通常用于治疗多重耐药细菌。我将评估耐利奈唑胺金黄色葡萄球菌细胞的分子缺陷，揭示可用于对抗这些耐药病原体的进化脆弱性。总的来说，这项研究可以帮助设计新的策略来减轻、预防或逆转抗菌素耐药性的演变。

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.