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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：
10432488
负责人：
Alexander Pak
金额：
$ 17.77万
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 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10432488
关键词：
Address Adhesions Adopted Affinity Anabolism Anthrax disease Antibiotic Resistance Antibiotic Therapy Antibiotics Antibodies Bacillus anthracis Bacteria Bacterial Antibiotic Resistance Behavior Binding Binding Proteins Biophysics 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 Risk Role Rupture Sampling Sequence Homology Solubility Stress Structure Surface Tertiary Protein Structure Testing Virulence Factors Virus Work antibiotic resistant infections antigen binding base biomacromolecule cell envelope cell growth combat combinatorial computer framework computerized tools crystallinity depolymerization design experimental study fight against fitness flexibility immunogenicity improved models and simulation molecular dynamics mouse model multi-scale modeling mutant nanobodies pathogen pathogenic bacteria prediction algorithm pressure prevent screening 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.

项目总结