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.

项目概要 生物膜本质上具有耐药性。虽然介导生物膜耐药性的信号通路已被记录， 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被人们认识到。然而，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 用于评估针对临床生物膜的治疗策略的杀菌潜力的筛选技术。 在 K99 培训期间，我将研究机械刺激的钙波动如何改变 c-di-GMP 池 （目标 1.1）和细菌群聚（目标 1.2）导致生物膜形成。与此同时，我将部署一个测定法来测量 以高通量检测生物膜的活力，以筛选针对生物膜的抗生素佐剂（目标 2.1）。在这个阶段，我的 培训将重点关注生物膜培养、非光学电生理学数据分析以及构建机器学习 随后在我的 R00 阶段应用了模型。 在 K99 阶段之后，我将使用光学和非光学研究成熟生物膜的电生理学 技术并将整个生物膜生命周期中抗生素耐受性的变化与电生理学的变化相关联（目标 1.3）。与此同时，我将建立和训练深度学习模型来预测庆大霉素佐剂对生长缓慢的细胞的作用 基于我在 K99 阶段收集的活力数据（目标 2.2）。 我的项目的产品将丰富我们对生物膜电生理学的理解，并提供缓解方法 它们的形成或促进它们的保留，这是益生菌所需要的。此外，这项工作还将交付新机器 学习寻找抗生素佐剂来对抗耐药临床生物膜的技术。