Multiscale Modeling of B. Anthracis Surface Layer Assembly and Depolymerization by Nanobodies

纳米抗体对炭疽杆菌表面层组装和解聚的多尺度建模

基本信息

批准号：
10615187
负责人：
Alexander Pak
金额：
$ 21.54万
依托单位：
COLORADO SCHOOL OF MINES
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：
2022-05-01 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10615187
关键词：
Address Adhesions Adopted Affinity Anabolism Anthrax disease Antibiotic Resistance Antibiotic Therapy Antibiotics Antibodies Bacillus anthracis Bacteria Bacterial Antibiotic Resistance Behavior Binding Biophysics Body Surface Capsid Proteins Cell Adhesion Cell Wall Cell membrane Centers for Disease Control and Prevention (U.S.)Characteristics Clostridium difficile Complementarity Determining Regions Computer Simulation Derivation procedure Engineering Epitopes Exhibits Free Energy Genetic Programming Goals Grain Health Health Care Costs Human Knowledge Mediating Mediation Microbiology Modeling Molecular Conformation Monoclonal Antibodies Mutation Nanoporous Outcome Pathogenesis Protein Biosynthesis Protein Engineering Proteins Protocols documentation Protomer Recombinants Reporting Rest Role Rupture Sampling Sequence Homology Solubility Stress Structure Surface Tertiary Protein Structure Testing Virulence Virulence Factors Virus Work antibiotic resistant infections antigen binding biomacromolecule cell envelope cell growth combat combinatorial computer framework computerized tools depolymerization design experimental study fighting fitness flexibility immunogenicity improved models and simulation molecular dynamics mouse model multi-scale modeling mutant nanobodies pathogen pathogenic bacteria prediction algorithm pressure prevent risk mitigation screening self assembly simulation therapeutic target two-dimensional

项目摘要

Project Summary Alternative strategies to conventional antibiotics are needed to combat rising antibiotic resistance in bacteria. Therapeutics that target virulence factors would instead disarm bacteria and mitigate the risk of developing antibiotic resistance. In this proposal, we investigate the disruption of bacterial surface layer proteins (SLPs), which self-assemble into a para-crystalline surface layer (S-layer), a virulence factor that mediates bacterial aggregation, adhesion, and protection. Nanobodies, which exhibit low immunogenicity in humans, and are easier to purify and deliver compared to monoclonal antibodies, were recently demonstrated to depolymerize S- layers in the case of Bacillus anthracis, which led to complete survival in mice models under sustained treatment. Our scientific premise is that nanobody-based inhibition of S-layers is a viable antivirulence strategy once tuned for each bacterial pathogen. We propose to leverage our multiscale computer simulation expertise to identify the as-yet unknown mechanism of action and to determine sequence motifs that enhance nanobody-induced S-layer depolymerization in Bacillus anthracis. Our aims include (1) verification that depolymerization is induced by S-layer rigidification through the use of coarse-grained modeling and simulation and (2) determination of nanobodies with improved antivirulence by computationally tailoring existing nanobodies. The computational protocols developed herein are systematic and generalizable beyond Bacillus anthracis. We expect our findings and computational tools to extend to other SLP-expressing bacteria, including urgent antibiotic-resistant threats such as Clostridioides difficile, and aid the global fight against antibiotic-resistant bacteria.

项目摘要需要采取常规抗生素的替代策略来对抗上升的抗生素细菌的抗性。靶向毒力因素的治疗剂将解除细菌并减轻产生抗生素耐药性的风险。在此提案中，我们调查了细菌表面层蛋白（SLP）的破坏，它们会自组装成para-crystalline 表面层（S层），一种介导细菌聚集，粘附和的毒力因子保护。纳米型在人类中表现出低免疫原性，并且更容易纯化与单克隆抗体相比，最近被证明可以解散S- 在炭疽芽孢杆菌的情况下，这导致了在小鼠模型中的完整生存持续治疗。我们的科学前提是，基于纳米的抑制S层是为每种细菌病原体调整了可行的抗毒素策略。我们建议利用我们的多尺度计算机模拟专业知识，以确定尚未知道的尚不清楚的机制动作并确定增强纳米型诱导的S层的序列基序炭疽芽孢杆菌的解聚。我们的目的包括（1）验证解聚是通过使用粗粒的建模和仿真以及（2）通过计算量身定制现有纳米体。本文开发的计算协议是系统的，可推广的超越炭疽芽孢杆菌。我们希望我们的发现和计算工具扩展到其他表达SLP的细菌，包括紧急抗生素的威胁，例如梭状芽胞杆菌艰难，并有助于全球反对抗生素耐药细菌的斗争。