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 项目总结 大多数抗生素对杀死休眠细菌无效，据估计，50%的抗生素耐药病例是由于 表型“持久性”而不是遗传耐药性：细菌可以在药物治疗中幸存下来，仅仅因为它们中的一小部分 在代谢上处于休眠状态。例如，生物膜中心的营养和氧气消耗使细菌 代谢处于休眠状态，对抗生素耐受。一旦停用抗生素，复发使细菌有机会 进化出抗生素抗药性。反复感染的常见例子包括致病性E。 大肠埃希氏菌--发达国家妇女最常见的细菌感染--潜伏性肺结核和生物被膜形成 细菌，如铜绿假单胞菌感染，往往会使伤口愈合复杂化，通常会影响囊性纤维化患者。 为了开发新的策略来对抗复发的感染和持久性，我们需要更好地理解休眠 细菌。 我的实验室旨在确定对休眠细菌有效的新抗生素靶标。通过研究自发 关于休眠细菌的死亡率，我们已经确定了关键的脆弱性。我们发现休眠细菌的死亡率 严重依赖于之前的增长条件。通过将蛋白质组学数据与死亡率相关联，我们已经确定 可能与休眠细菌的生存和适应过程有关的数百个基因。我们已经验证了许多 我们的候选者利用遗传学，发现了细菌外膜对休眠生存至关重要的作用 细菌。我们现在需要揭示外膜如何在休眠期间机械地帮助生存和 了解我们已经发现的细胞膜、渗透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组合 针对休眠细菌的现有药物。我的实验室在数量生物学和生物物理学方面的跨学科经验 我们有一个独特的位置来回答这些问题，并提供对休眠状态的生理学的关键见解。

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 Once the antibiotic is withdrawn, recurrence gives bacteria the chance to evolve antibiotic resistance.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.