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:
- 金额:$ 21.54万
- 依托单位:
- 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:
- 关键词:AddressAdhesionsAdoptedAffinityAnabolismAnthrax diseaseAntibiotic ResistanceAntibiotic TherapyAntibioticsAntibodiesBacillus anthracisBacteriaBacterial Antibiotic ResistanceBehaviorBindingBiophysicsBody SurfaceCapsid ProteinsCell AdhesionCell WallCell membraneCenters for Disease Control and Prevention (U.S.)CharacteristicsClostridium difficileComplementarity Determining RegionsComputer SimulationDerivation procedureEngineeringEpitopesExhibitsFree EnergyGenetic ProgrammingGoalsGrainHealthHealth Care CostsHumanKnowledgeMediatingMediationMicrobiologyModelingMolecular ConformationMonoclonal AntibodiesMutationNanoporousOutcomePathogenesisProtein BiosynthesisProtein EngineeringProteinsProtocols documentationProtomerRecombinantsReportingRestRoleRuptureSamplingSequence HomologySolubilityStressStructureSurfaceTertiary Protein StructureTestingVirulenceVirulence FactorsVirusWorkantibiotic resistant infectionsantigen bindingbiomacromoleculecell envelopecell growthcombatcombinatorialcomputer frameworkcomputerized toolsdepolymerizationdesignexperimental studyfightingfitnessflexibilityimmunogenicityimprovedmodels and simulationmolecular dynamicsmouse modelmulti-scale modelingmutantnanobodiespathogenpathogenic bacteriaprediction algorithmpressurepreventrisk mitigationscreeningself assemblysimulationtherapeutic targettwo-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
需要传统抗生素的替代策略来对抗日益增长的抗生素
细菌中的抗药性。针对毒力因子的疗法将取而代之解除细菌的武装
并减轻产生抗生素耐药性的风险。在这份提案中,我们调查了
破坏细菌表面层蛋白(SLP),这些蛋白自组装成类晶体
表层(S层),一种介导细菌聚集、黏附和
保护。纳米抗体,在人类中表现出低免疫原性,更容易纯化
并与单抗相比,最近被证明能解聚S-
在炭疽芽孢杆菌的情况下,这导致了在小鼠模型中完全存活
持续治疗。我们的科学前提是,基于纳米体的S层的抑制是一种
可行的抗病毒策略曾经针对每种细菌病原体进行了调整。我们建议利用
我们的多尺度计算机模拟专业知识,以确定迄今未知的机制
作用并确定增强纳米体诱导的S层的序列基序
炭疽芽孢杆菌的解聚作用。我们的目标包括(1)验证解聚是
通过使用粗粒度建模和模拟,诱导S-层硬化
(2)通过计算裁剪现有的纳米体来确定具有改进的抗病毒力的纳米体
纳米物体。这里开发的计算协议是系统的和可推广的
超越了炭疽芽孢杆菌。我们希望我们的发现和计算工具能够扩展到其他
表达SLP的细菌,包括紧急的抗生素耐药性威胁,如梭状芽胞杆菌
艰难梭菌,并帮助全球抗击抗药性细菌。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
Alexander Pak其他文献
Alexander Pak的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('Alexander Pak', 18)}}的其他基金
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
- 批准号:
10432488 - 财政年份:2022
- 资助金额:
$ 21.54万 - 项目类别:
Computational Insights into Assembly, Budding, and Maturation during HIV-1 Replication
HIV-1 复制过程中组装、出芽和成熟的计算见解
- 批准号:
9754846 - 财政年份:2017
- 资助金额:
$ 21.54万 - 项目类别:
Computational Insights into Assembly, Budding, and Maturation during HIV-1 Replication
HIV-1 复制过程中组装、出芽和成熟的计算见解
- 批准号:
9396905 - 财政年份:2017
- 资助金额:
$ 21.54万 - 项目类别:
相似海外基金
How tensins transform focal adhesions into fibrillar adhesions and phase separate to form new adhesion signalling hubs.
张力蛋白如何将粘着斑转化为纤维状粘连并相分离以形成新的粘连信号中枢。
- 批准号:
BB/Y004841/1 - 财政年份:2024
- 资助金额:
$ 21.54万 - 项目类别:
Research Grant
Defining a role for non-canonical mTORC1 activity at focal adhesions
定义非典型 mTORC1 活性在粘着斑中的作用
- 批准号:
BB/Y001427/1 - 财政年份:2024
- 资助金额:
$ 21.54万 - 项目类别:
Research Grant
How tensins transform focal adhesions into fibrillar adhesions and phase separate to form new adhesion signalling hubs.
张力蛋白如何将粘着斑转化为纤维状粘连并相分离以形成新的粘连信号中枢。
- 批准号:
BB/Y005414/1 - 财政年份:2024
- 资助金额:
$ 21.54万 - 项目类别:
Research Grant
Development of a single-use, ready-to-use, sterile, dual chamber, dual syringe sprayable hydrogel to prevent postsurgical cardiac adhesions.
开发一次性、即用型、无菌、双室、双注射器可喷雾水凝胶,以防止术后心脏粘连。
- 批准号:
10669829 - 财政年份:2023
- 资助金额:
$ 21.54万 - 项目类别:
Regulating axon guidance through local translation at adhesions
通过粘连处的局部翻译调节轴突引导
- 批准号:
10587090 - 财政年份:2023
- 资助金额:
$ 21.54万 - 项目类别:
Improving Maternal Outcomes of Cesarean Delivery with the Prevention of Postoperative Adhesions
通过预防术后粘连改善剖宫产的产妇结局
- 批准号:
10821599 - 财政年份:2023
- 资助金额:
$ 21.54万 - 项目类别:
Regulating axon guidance through local translation at adhesions
通过粘连处的局部翻译调节轴突引导
- 批准号:
10841832 - 财政年份:2023
- 资助金额:
$ 21.54万 - 项目类别:
Prevention of Intraabdominal Adhesions via Release of Novel Anti-Inflammatory from Surface Eroding Polymer Solid Barrier
通过从表面侵蚀聚合物固体屏障中释放新型抗炎剂来预防腹内粘连
- 批准号:
10532480 - 财政年份:2022
- 资助金额:
$ 21.54万 - 项目类别:
I-Corps: A Sprayable Tissue-Binding Hydrogel to Prevent Postsurgical Cardiac Adhesions
I-Corps:一种可喷雾的组织结合水凝胶,可防止术后心脏粘连
- 批准号:
10741261 - 财政年份:2022
- 资助金额:
$ 21.54万 - 项目类别:
Sprayable Polymer Blends for Prevention of Site Specific Surgical Adhesions
用于预防特定部位手术粘连的可喷涂聚合物共混物
- 批准号:
10674894 - 财政年份:2022
- 资助金额:
$ 21.54万 - 项目类别: