Is inhibiting pili electrical conductivity a new anti-virulence strategy?

抑制菌毛导电性是一种新的抗毒策略吗？

基本信息

批准号：
10387218
负责人：
Matthew J. Guberman-pfeffer
金额：
$ 6.76万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-01-01 至 2022-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10387218
关键词：
Adhesions Adhesiveness Adhesives Antibiotic Resistance Bacteria Bacterial Adhesion Bacterial Pili Binding Sites Biochemistry Biophysics Cells Charge Chemistry Collaborations Communities Dangerousness Development Development Plans Docking Educational workshop Electric Conductivity Electron Transport Electrons Fellowship Filament Free Energy Infection Institutes Intestines Journals Ligands Mechanics Mediating Mentors Mentorship Microbial Biofilms Molecular Molecular Conformation Mutation Nature Outcome Pathogenicity Pilum Play Point Mutation Population Process Property Pseudomonas aeruginosa Publishing Pulmonary Cystic Fibrosis Research Resistance Role Science Structure Surface Techniques Tensile Strength Theoretical model Therapeutic Thinness Training Universities Virulence Work adhesion process antagonist antimicrobial career development chronic infection cystic fibrosis patients design drug discovery electrical property extracellular graduate student high throughput screening host-microbe interactions human pathogen insight interfacial kinetic model microbial microbial community microbiota molecular dynamics nanowire novel therapeutics pathogen pathogenic bacteria pressure prevent professor prospective quantum rational design receptor small molecule success symposium theories treatment strategy

项目摘要

Project Summary Adhesion of bacteria to host cells is an essential step in the initiation of an infection, and yet, the mechanisms that make bacteria sticky are not fully understood. A long list of human pathogens, including Pseudomonas aeruginosa in the lungs of cystic fibrosis patients, become anchored to host cells using thin (<10 nm), long (>1 µm), and mechanically strong (capable of withstanding pN to nN forces) filaments called pili. The pili latch onto surfaces through receptor-ligand interactions, and only very recently discovered, extracellular electron transfer. Bacteria with more electrically conductive pili tend to be more adhesive. By elucidating the mechanistic basis for this observation, we seek to establish design rules for manipulating microbe-host interactions for therapeutic purposes. New therapies that inhibit pili-mediated charge transfer could be realized to block the formation of biofilms by pathogenic species, or to correct imbalances in the populations of adhered intestinal tract microbiota. To realize these possibilities, we specifically aim to establish the relative contributions of mechanical and electrical mechanisms in bacterial adhesion mediated by pili. Alchemical and steered molecular dynamics simulations will be used to assess the change in stability and tensile strength of pili as a function of point mutations associated with differently adherent bacteria. A quantum mechanical/molecular mechanical implementation of Marcus theory, combined with a kinetic model, will be used to compute the electrical conductivity of different pili. The pili will feature mutations according to a direct electronic modulation strategy: Standard residues will be replaced with substituent-bearing unnatural counterparts that have similar steric but different electronic properties. The obtained structure-function insights will drive the second aim of our research to rationally design and evaluate pili antagonists. Fragment dissolved molecular dynamics will be used to identify prospective binding sites, into which ligands will be docked in a high throughput screen and optimized by free energy perturbation techniques. The work will be undertaken at Yale University under the mentorship of Professor Nikhil S. Malvankar of the Microbial Science Institute within the Molecular Biophysics and Biochemistry department, and in collaboration with John Randolph Huffman Professor Victor S. Batista of the Chemistry department. Their combined expertise with bacterial nanowires (Dr. Malvankar) and the theoretical modeling of interfacial electron transfer processes (Dr. Batista) will serve as unique assists for the success of the project. The fellowship training plan involves publishing in high impact journals and presenting at conferences for the biomedical and chemistry communities. It also includes the opportunity to mentor graduate students. The career development plan includes attending professional development workshops organized by the Office of Postdoctoral Affairs, as well as courses relevant to the project.

项目摘要细菌对宿主细胞的粘附是感染倡议的重要步骤，但是，使细菌粘性的机制尚不完全了解。一长串人类病原体，包括囊性纤维化患者肺中铜绿假单胞菌的铜绿假单胞菌使用薄（<10）锚定在宿主细胞上（<10 nm），长（> 1 µm）和机械强（能够承受pn到Nn力）的丝，称为pili。通过受体配体的相互作用，壁块闩锁在表面上，直到最近才发现细胞外电子转移。具有更具导电性菌毛的细菌往往更具粘性。经过阐明该观察的机械基础，我们试图建立操纵的设计规则用于治疗目的的微生物 - 宿主相互作用。抑制pili介导的电荷转移的新疗法可以实现通过致病物种阻止生物膜的形成，或纠正粘附的肠道微生物群的种群。为了实现这些可能性，我们特别旨在建立机械的相对贡献和细菌粘附中的电机理。炼金术和蒸分子动力学模拟将用于评估pili的稳定性和拉伸强度的变化作为点的函数与不同粘附细菌相关的突变。量子机械/分子机械 Marcus理论的实施以及动力学模型将用于计算电气不同pili的电导率。 pili将根据直接电子调制具有突变策略：标准残差将被具有相似的宽大不自然对应物取代空间但不同的电子特性。获得的结构功能见解将推动我们对合理设计和评估pili拮抗剂的研究。碎片溶解的分子动力学将是用于识别前瞻性绑定位点，将配体在高吞吐量屏幕中停靠在其中通过自由能扰动技术优化。这项工作将在耶鲁大学的尼克希尔·S·马尔万卡教授的指导下在耶鲁大学进行。分子生物物理学和生物化学系中的微生物科学研究所，在与化学系的John Randolph Huffman教授Victor S. Batista合作。他们的与细菌纳米线（Malvankar博士）和界面的理论建模相结合的专业知识电子转移过程（Batista博士）将作为该项目成功的独特助攻。奖学金培训计划涉及在高影响期刊上发布，并在会议上介绍生物医学和化学社区。它还包括智力研究生的机会。这职业发展计划包括参加由办公室组织的专业发展研讨会博士后事务以及与该项目相关的课程。