The electrophysiology of biofilm development and drug resistance

生物膜发育和耐药性的电生理学

• 批准号: 10740493
• 负责人: Christian T Meyer
• 金额: $ 13.87万
• 依托单位: UNIVERSITY OF COLORADO
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-06 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10740493
• 关键词: Address; Adjuvant; Aminoglycoside resistance; Aminoglycosides; Antibiotics; Bacteria; Basic Science; Biological Assay; Biotechnology; COVID-19; Calcium; Cell Survival; Cells; Cessation of life; Chemical Structure; Clinic; Clinical; Combined Antibiotics; Complex; DNA Sequence Alteration; DNA biosynthesis; Data; Development; Dimensions; Drug Combinations; Drug Synergism; Drug resistance; Electrophysiology (science); Gene Combinations; Gentamicins; Growth; Hospitals; Infection; Intervention; Life Cycle Stages; Machine Learning; Measurement; Measures; Mechanical Stimulation; Mechanics; Mediating; Metabolic; Methods; Microbial Biofilms; Morphology; Optics; Outcome; Pharmaceutical Preparations; Phase; Physiological; Physiology; Positioning Attribute; Postdoctoral Fellow; Predictive Value; Probiotics; Refractory; Resistance; Role; Signal Pathway; Speed; Suspensions; Techniques; Technology; Testing; Therapeutic; Training; Urinary tract infection; Work; antibiotic resistant infections; antibiotic tolerance; bactericide; cell motility; combat; combinatorial; commune; deep learning; deep learning model; density; drug resistant pathogen; high throughput screening; in silico; innovation; insight; invention; knockout gene; machine learning model; minimal inhibitory concentration; multi-electrode arrays; new technology; non-genetic; novel drug combination; novel therapeutic intervention; pre-clinical; preempt; screening; sensor; soft tissue; synergism; technology development; treatment strategy

Project Summary Biofilms are intrinsically drug-resistant. While the signaling pathways mediating resistance in biofilms are documented, only recently has the importance of electrophysiology in modifying gentamicin resistance come to light. However, the role of electrophysiology in biofilm formation and maturation is unknown. Furthermore, we currently lack high throughput screening techniques for assessing the bactericidal potential of treatment strategies against clinical biofilms. During my K99 training, I will investigate how mechanically-stimulated calcium fluctuations modify the c-di-GMP pools (Aim 1.1) and bacterial swarming (Aim 1.2) leading to biofilm formation. Concomitantly, I will deploy an assay for measur- ing biofilm viability in high throughput to screen for antibiotic adjuvants against biofilms (Aim 2.1). During this phase, my training will focus on the culture of biofilms, analysis of non-optical electrophysiology data, and building machine learning models subsequently applied during my R00 phase. Following my K99 phase, I will investigate the electrophysiology of mature biofilms using both optical and non-optical techniques and correlate changes in antibiotic tolerance across the biofilm life-cycle with changes in electrophysiology (Aim 1.3). Concomitantly, I will build and train deep learning models to predict gentamicin adjuvants against slow-growing cells based on viability data collected in my K99 phase (Aim 2.2). The product of my project will enrich our understanding of biofilm electrophysiology and enable methods for mitigating their formation or promoting their retention as is desirable for probiotics. Additionally, this work will deliver new machine learning technologies for finding antibiotic adjuvants to combat drug-resistant clinical biofilms.

项目摘要 生物被膜本质上是耐药的。虽然介导生物膜耐药的信号通路已有文献记载， 直到最近，电生理学在改变庆大霉素耐药性方面的重要性才浮出水面。然而，这个角色 电生理学在生物膜形成和成熟中的作用尚不清楚。此外，我们目前缺乏高吞吐量 评估针对临床生物被膜的治疗策略杀菌潜力的筛选技术。 在我的K99训练期间，我将研究机械刺激的钙波动是如何改变c-di-GMP池的。 (目标1.1)和细菌聚集(目标1.2)导致生物膜形成。随之而来的是，我将部署一种测试方法来测量- 在高通量下检测生物被膜的活性，以筛选抗生物被膜的抗生素佐剂(目标2.1)。在这一阶段，我的 培训将侧重于生物膜的培养、非光学电生理学数据的分析以及建立机器学习 后来在我的R00阶段应用了一些模型。 在我的K99阶段之后，我将使用光学和非光学两种方法研究成熟生物膜的电生理学 生物膜生命周期中抗生素耐受性的变化与电生理学变化的技术和相关性(目的 1.3)。与此同时，我将建立和训练深度学习模型，以预测庆大霉素佐剂对生长缓慢的细胞的作用 基于在我的K99阶段(目标2.2)收集的生存能力数据。 我的项目的成果将丰富我们对生物膜电生理学的理解，并使缓解 它们的形成或促进它们的保留对于益生菌是可取的。此外，这项工作将交付新的机器 寻找抗生素佐剂以对抗耐药临床生物被膜的学习技术。