Elucidating physiology of dormant bacteria to combat antibiotic persistence

应用程序标题 阐明休眠细菌的生理学以对抗抗生素持久性 项目摘要 大多数抗生素对杀死休眠细菌无效，据估计，50%的抗生素耐药性病例是由于 表型“持久性”而不是遗传抗性：细菌可以在药物治疗中存活，仅仅是因为其中一些细菌 都处于新陈代谢休眠状态例如，生物膜中心的营养物和氧气消耗使得细菌 代谢休眠和抗生素耐受。一旦停用抗生素，复发就会给细菌提供机会， 进化出抗生素耐药性。复发性感染的常见例子包括致病性大肠杆菌的尿路感染。 大肠杆菌-发达国家妇女最常见的细菌感染-潜伏性结核病和生物膜形成 细菌，如铜绿假单胞菌感染，往往使伤口愈合复杂化，通常影响囊性纤维化患者。 为了制定新的战略来对抗复发性感染和持久性，我们需要更好地了解休眠期感染。 细菌 我的实验室旨在确定新的抗生素靶点，有效对抗休眠细菌。通过研究自发的 休眠细菌的死亡率，我们已经确定了关键的弱点。我们发现休眠细菌的死亡率 主要取决于以前的生长条件。通过将蛋白质组学数据与死亡率相关联， 数百个基因可能有助于休眠细菌的生存和适应过程。我们已经验证了许多 我们的候选人使用遗传学，并发现了一个关键作用的细菌外膜的生存休眠 细菌我们现在需要揭示外膜如何在休眠期间机械地有助于生存， 了解我们发现的细胞包膜、细胞周期调节和能量代谢之间的复杂相互作用。 对这些过程的更好理解将揭示最有希望的抗生素靶点和有效的抗生素组合。 针对休眠细菌的现有药物我实验室在定量生物学和生物物理学方面的跨学科经验 我们在一个独特的位置来回答这些问题，并提供关键的见解休眠状态的生理学。

APPLICATION TITLE Elucidating physiology of dormant bacteria to combat antibiotic persistence PROJECT SUMMARY Most antibiotics are ineffective for killing dormant bacteria and it is estimated that 50% of antibiotic tolerance cases are due to phenotypic `persistence' rather than genetic resistance: bacteria can survive drug treatment simply because a few of them are metabolically dormant. For example, nutrient and oxygen depletion in the center of biofilms renders bacteria metabolically dormant and antibiotic tolerant. Once the antibiotic is withdrawn, recurrence gives bacteria the chance to evolve antibiotic resistance. Common examples of recurrent infections include urinary tract infections of pathogenic E. coli—the most common bacterial infection in women in developed countries—latent tuberculosis, and biofilm-forming bacteria, like the P. aeruginosa infections that often complicate wound healing and commonly affect cystic fibrosis patients. To develop new strategies to combat recurring infections and persistence, we need a better understanding of dormant bacteria. My laboratory aims to identify new antibiotic targets that are effective against dormant bacteria. By studying spontaneous death rates of dormant bacteria, we have already identified key vulnerabilities. We found that death rates of dormant bacteria critically depend on previous growth conditions. By correlating proteomics data with death rates, we have identified hundreds of genes that may contribute to survival and adaptation processes of dormant bacteria. We have validated many of our candidates using genetics, and discovered a crucial role of the bacterial outer membrane for the survival of dormant bacteria. We now need to uncover how the outer membrane mechanistically contributes to survival during dormancy and understand a complex interplay between the cell envelope, osmoregulation and energy metabolism that we have discovered. A better understanding of these processes will reveal the most promising antibiotic targets and effective combinations of existing drugs against dormant bacteria. My lab's interdisciplinary experience in quantitative biology and biophysics puts us in a unique position to answer these questions and to provide key insights into the physiology of dormant states.