Elucidating physiology of dormant bacteria to combat antibiotic persistence

阐明休眠细菌的生理学以对抗抗生素的持久性

• 批准号: 10684872
• 负责人: Markus Thomas Basan
• 金额: $ 41.74万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10684872
• 关键词: Affect; Antibiotic Resistance; Antibiotics; Bacteria; Bacterial Infections; Biology; Biophysics; Cause of Death; Complex; Data; Death Rate; Developed Countries; Effectiveness; Energy Metabolism; Escherichia coli; Genes; Genetic; Growth; Laboratories; Membrane; Metabolic; Microbial Biofilms; Molecular; Nutrient; Osmoregulation; Oxygen; Pathogenesis; Pharmaceutical Preparations; Pharmacotherapy; Phenotype; Physiology; Positioning Attribute; Process; Proteomics; Pseudomonas aeruginosa infection; Recurrence; Role; Tuberculosis; Urinary tract infection; Woman; antibiotic tolerance; cell envelope; combat; cystic fibrosis patients; experience; genetic resistance; insight; novel; pathogenic Escherichia coli; recurrent infection; wound healing

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 Once the antibiotic is withdrawn, recurrence gives bacteria the chance to evolve antibiotic resistance.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

申请标题 阐明休眠细菌的生理学以对抗抗生素的持久性 项目概要 大多数抗生素无法有效杀死休眠细菌，估计 50% 的抗生素耐受病例是由于 表型“持久性”而不是遗传抗性：细菌能够在药物治疗中存活下来，仅仅是因为其中少数细菌 处于代谢休眠状态。例如，生物膜中心的营养物质和氧气消耗使得细菌 代谢休眠和抗生素耐受。一旦抗生素被撤除，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——发达国家女性中最常见的细菌感染——潜伏性结核病和生物膜形成 细菌，如铜绿假单胞菌感染，常常使伤口愈合复杂化，并通常影响囊性纤维化患者。 为了制定新策略来对抗反复感染和持续感染，我们需要更好地了解休眠病毒 细菌。 我的实验室旨在确定可有效对抗休眠细菌的新抗生素靶点。通过研究自发 休眠细菌的死亡率，我们已经确定了关键的漏洞。我们发现休眠细菌的死亡率 关键取决于之前的生长条件。通过将蛋白质组学数据与死亡率相关联，我们发现 数百个可能有助于休眠细菌的生存和适应过程的基因。我们已经验证了很多 我们的候选者利用遗传学进行了研究，发现细菌外膜对于休眠细菌的生存起着至关重要的作用 细菌。我们现在需要揭示外膜如何在机制上有助于休眠期间的生存和 了解我们发现的细胞包膜、渗透调节和能量代谢之间复杂的相互作用。 更好地了解这些过程将揭示最有希望的抗生素靶点和有效的组合 现有的针对休眠细菌的药物。我的实验室在定量生物学和生物物理学方面的跨学科经验 我们处于独特的地位来回答这些问题并提供对休眠状态生理学的重要见解。

项目成果

A semiconductor 96-microplate platform for electrical-imaging based high-throughput phenotypic screening.

• DOI: 10.1038/s41467-023-43333-9
• 发表时间: 2023-11-21
• 期刊: NATURE COMMUNICATIONS
• 影响因子: 16.6
• 作者: Chitale, Shalaka;Wu, Wenxuan;Mukherjee, Avik;Lannon, Herbert;Suresh, Pooja;Nag, Ishan;Ambrosi, Christina M.;Gertner, Rona S.;Melo, Hendrick;Powers, Brendan;Wilkins, Hollin;Hinton, Henry;Cheah, Michael;Boynton, Zachariah G.;Alexeyev, Alexander;Sword, Duane;Basan, Markus;Park, Hongkun;Ham, Donhee;Abbott, Jeffrey
• 通讯作者: Abbott, Jeffrey

Long-term history dependence of growth rates of E. coli after nutrient shifts.

营养物质变化后大肠杆菌生长率的长期历史依赖性。

• DOI: 10.1101/2023.08.22.554350
• 发表时间: 2023
• 期刊: bioRxiv : the preprint server for biology
• 作者: Christodoulou,Dimitris;Mukherjee,Avik;Wegmann,Rebekka;Pagano,Adriano;Sharma,Varun;Linker,StephanieMaria;Chang,Yu-Fang;Palme,JuliusSebastian;Sauer,Uwe;Basan,Markus
• 通讯作者: Basan,Markus

Multi-parametric functional imaging of cell cultures and tissues with a CMOS microelectrode array.

• DOI: 10.1039/d1lc00878a
• 发表时间: 2022-03-29
• 期刊: Lab on a chip
• 影响因子: 6.1
• 作者: Abbott J;Mukherjee A;Wu W;Ye T;Jung HS;Cheung KM;Gertner RS;Basan M;Ham D;Park H
• 通讯作者: Park H

MetA is a "thermal fuse" that inhibits growth and protects Escherichia coli at elevated temperatures.

• DOI: 10.1016/j.celrep.2022.111290
• 发表时间: 2022-08-30
• 期刊: CELL REPORTS
• 影响因子: 8.8
• 作者: Schink, Severin J.;Gough, Zara;Biselli, Elena;Huiman, Mariel Garcia;Chang, Yu-Fang;Basan, Markus;Gerland, Ulrich
• 通讯作者: Gerland, Ulrich

Glycolysis/gluconeogenesis specialization in microbes is driven by biochemical constraints of flux sensing.

微生物中的糖酵解/糖异生的专业化是由通量感应的生化约束驱动的。

• DOI: 10.15252/msb.202110704
• 发表时间: 2022-01
• 期刊: Molecular systems biology
• 影响因子: 9.9
• 作者: Schink SJ;Christodoulou D;Mukherjee A;Athaide E;Brunner V;Fuhrer T;Bradshaw GA;Sauer U;Basan M
• 通讯作者: Basan M