Cell Envelope Biogenesis in Clostridioides difficile
艰难梭菌的细胞包膜生物发生
基本信息
- 批准号:10414113
- 负责人:
- 金额:$ 51.42万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-06-01 至 2026-05-31
- 项目状态:未结题
- 来源:
- 关键词:AddressAnimal ModelAntibiotic ResistanceAntibiotic TherapyAntibioticsAttentionBacteriaBiochemistryBiogenesisBiologyCRISPR interferenceCarboxypeptidaseCategoriesCell WallCell divisionCellular MorphologyCellular biologyCenters for Disease Control and Prevention (U.S.)Cessation of lifeClostridium difficileColonComplexEnzymesEssential GenesFluorescence MicroscopyFoundationsGene DeletionGene ExpressionGene SilencingGenesGeneticGenetic TranscriptionGenomeGlucosamineGoalsGrowthHealthHomeostasisHospital NursingHumanIn SituIndividualInfectionInvestigationKnowledgeLabelLeadLibrariesMapsMasksMicroscopyMorphologyNursing HomesOrganismPPBP genePathway interactionsPenicillin-Binding ProteinsPeptidesPeptidoglycanPeptidyltransferasePersonsProcessProteinsPublic HealthRegulationReproduction sporesRoleSeedsSiteSystemTestingUnited StatesVancomycinbasebeta-Lactamscell assemblycell envelopecombatcrosslinkexperimental studyglycosyltransferasegut bacteriainsightmicrobiotanew therapeutic targetnovelnovel strategiespathogenpreventtool
项目摘要
Project Summary
Clostridioides (Clostridium) difficile infections of the colon strike close to 500,000 people a year in the United
States, leading to nearly 30,000 deaths. The CDC has declared this organism an “urgent” threat to public health,
the highest threat category. C. difficile infections are difficult to treat in large part because the organism forms
dormant spores that survive antibiotic therapy and seed recolonization of the gut when antibiotics are withdrawn.
This problem is exacerbated by the fact that the antibiotics used against C. difficile also kill many of the healthy
gut bacteria, clearing the way for C. difficile to recolonize when spores germinate. Thus, there is a tremendous
need for new drugs that target C. difficile without disrupting the healthy microbiota. The premise of this proposal
is that a deeper understanding of cell envelope biogenesis can pave the way towards developing better ways to
treat C. difficile infections. The cell envelope is a well-validated target for antibiotics, and in C. difficile the
envelope has some unusual features that suggest its assembly requires novel proteins that could be exploited
as targets of C. difficile-selective antibiotics. In Aim 1 we will use genetics, biochemistry and microscopy to
understand the roles and regulation of enzymes that crosslink the peptidoglycan cell wall. These enzymes
captured our attention because in C. difficile the cell wall contains an unusually high percentage of “3-3”
crosslinks as compared to the “4-3” crosslinks that predominate in most bacteria. Our experiments will address
the following questions: Which enzymes are responsible for 3-3 and 4-3 crosslink formation and do they operate
during division, elongation or both? How is the ratio of 3-3 to 4-3 crosslinking regulated? How does C. difficile
benefit from using primarily 3-3 crosslinks? In Aim 2 we will leverage a powerful new gene-silencing tool called
CRISPR interference (CRISPRi) to assign a set of ~50 putatively essential envelope biogenesis genes to more
specific functional pathways. These genes are intrinsically interesting and constitute potential new antibiotic
targets. We will also undertake a detailed analysis of a novel transcriptional regulatory system uncovered in a
pilot version of our proposed screen. Collectively, the lines of investigation to be pursued here will greatly
advance our understanding of C. difficile biology by identifying new proteins involved in assembly of the cell
envelope and revealing how their activities are coordinated to accomplish the complex processes of growth and
division.
项目摘要
在美国,每年有近50万人感染结肠艰难梭菌。
导致近3万人死亡。疾病预防控制中心宣布这种微生物对公共卫生构成“紧急”威胁,
最高的威胁类别。C.难治性感染很难治疗,
休眠孢子,在抗生素治疗和停止使用抗生素后肠道的种子繁殖中存活下来。
这一问题因针对C.艰难梭菌也会杀死许多健康的
肠道细菌,为C.当孢子萌发时很难形成孢子。因此,
需要针对C的新药。而不会破坏健康的微生物群。这项提议的前提是
更深入地了解细胞包膜生物发生可以为开发更好的方法铺平道路,
治疗C.艰难感染。细胞被膜是抗生素的有效靶点,在C。艰难的
包膜有一些不寻常的特征,这表明它的组装需要新的蛋白质,
作为C.难选抗生素在目标1中,我们将使用遗传学、生物化学和显微镜技术,
了解交联肽聚糖细胞壁的酶的作用和调节。这些酶
吸引了我们的注意力,因为在C。difficile细胞壁含有异常高的“3-3”百分比,
与在大多数细菌中占主导地位的“4-3”交联相比,我们的实验将解决
以下问题:哪些酶负责3-3和4-3交联的形成,它们是否起作用
在分裂、伸长或两者的过程中?3-3与4-3交联的比例如何调节?C.艰难
主要使用3-3个交叉链接的好处?在目标2中,我们将利用一种强大的新基因沉默工具,
CRISPR干扰(CRISPRi)将一组约50个puerectin必需的包膜生物发生基因分配给更多
特定的功能路径。这些基因本质上是有趣的,并构成潜在的新抗生素
目标的我们还将对一个新的转录调控系统进行详细的分析,该系统是在一个
我们提议的屏幕的试点版本。总的来说,在这里进行的调查将大大
加深了对C.通过识别参与细胞组装的新蛋白质,
信封和揭示他们的活动是如何协调,以完成复杂的增长过程,
师.
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 }}
Craig D Ellermeier其他文献
Activation of the extracytoplasmic function σ factor σsupV/sup by lysozyme in emClostridioides difficile/em
溶菌酶在艰难梭菌中激活胞外功能σ因子σsupV/sup
- DOI:
10.1016/j.mib.2021.11.008 - 发表时间:
2022-02-01 - 期刊:
- 影响因子:7.500
- 作者:
Theresa D Ho;Craig D Ellermeier - 通讯作者:
Craig D Ellermeier
Craig D Ellermeier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('Craig D Ellermeier', 18)}}的其他基金
Regulation of the C. difficile cell envelope by Two-component systems
双组分系统对艰难梭菌细胞包膜的调节
- 批准号:
10368150 - 财政年份:2021
- 资助金额:
$ 51.42万 - 项目类别:
Cell Envelope Biogenesis in Clostridioides difficile
艰难梭菌的细胞包膜生物发生
- 批准号:
10626841 - 财政年份:2021
- 资助金额:
$ 51.42万 - 项目类别:
Cell Envelope Biogenesis in Clostridioides difficile
艰难梭菌的细胞包膜生物发生
- 批准号:
10295470 - 财政年份:2021
- 资助金额:
$ 51.42万 - 项目类别:
Regulation of the C. difficile cell envelope by Two-component systems
双组分系统对艰难梭菌细胞包膜的调节
- 批准号:
10189921 - 财政年份:2021
- 资助金额:
$ 51.42万 - 项目类别:
Extra-Cytoplasmic Function Sigma Factor Senses and Responds to Beta-Lactam Stress in Gram-Positive Bacteria
细胞质外功能 Sigma 因子感知并响应革兰氏阳性细菌中的 β-内酰胺应激
- 批准号:
9805086 - 财政年份:2019
- 资助金额:
$ 51.42万 - 项目类别:
Regulation of toxin gene expression in Clostridium difficile
艰难梭菌毒素基因表达的调控
- 批准号:
9180099 - 财政年份:2016
- 资助金额:
$ 51.42万 - 项目类别:
ECF Sigma Factors and the Cell Envelope Stress Response of Clostridium difficile
ECF Sigma 因子和艰难梭菌的细胞包膜应激反应
- 批准号:
8417706 - 财政年份:2011
- 资助金额:
$ 51.42万 - 项目类别:
ECF Sigma Factors and the Cell Envelope Stress Response of Clostridium difficile
ECF Sigma 因子和艰难梭菌的细胞包膜应激反应
- 批准号:
8222807 - 财政年份:2011
- 资助金额:
$ 51.42万 - 项目类别:
Identification of daptomycin resistance mechanisms in Clostridioides difficile
艰难梭菌达托霉素耐药机制的鉴定
- 批准号:
10688123 - 财政年份:2011
- 资助金额:
$ 51.42万 - 项目类别:
ECF Sigma Factors and the Cell Envelope Stress Response of Clostridium difficile
ECF Sigma 因子和艰难梭菌的细胞包膜应激反应
- 批准号:
8791587 - 财政年份:2011
- 资助金额:
$ 51.42万 - 项目类别:
相似海外基金
Quantification of Neurovasculature Changes in a Post-Hemorrhagic Stroke Animal-Model
出血性中风后动物模型中神经血管变化的量化
- 批准号:
495434 - 财政年份:2023
- 资助金额:
$ 51.42万 - 项目类别:
Small animal model for evaluating the impacts of cleft lip repairing scar on craniofacial growth and development
评价唇裂修复疤痕对颅面生长发育影响的小动物模型
- 批准号:
10642519 - 财政年份:2023
- 资助金额:
$ 51.42万 - 项目类别:
Bioactive Injectable Cell Scaffold for Meniscus Injury Repair in a Large Animal Model
用于大型动物模型半月板损伤修复的生物活性可注射细胞支架
- 批准号:
10586596 - 财政年份:2023
- 资助金额:
$ 51.42万 - 项目类别:
A Comparison of Treatment Strategies for Recovery of Swallow and Swallow-Respiratory Coupling Following a Prolonged Liquid Diet in a Young Animal Model
幼年动物模型中长期流质饮食后吞咽恢复和吞咽呼吸耦合治疗策略的比较
- 批准号:
10590479 - 财政年份:2023
- 资助金额:
$ 51.42万 - 项目类别:
Diurnal grass rats as a novel animal model of seasonal affective disorder
昼夜草鼠作为季节性情感障碍的新型动物模型
- 批准号:
23K06011 - 财政年份:2023
- 资助金额:
$ 51.42万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Longitudinal Ocular Changes in Naturally Occurring Glaucoma Animal Model
自然发生的青光眼动物模型的纵向眼部变化
- 批准号:
10682117 - 财政年份:2023
- 资助金额:
$ 51.42万 - 项目类别:
A whole animal model for investigation of ingested nanoplastic mixtures and effects on genomic integrity and health
用于研究摄入的纳米塑料混合物及其对基因组完整性和健康影响的整体动物模型
- 批准号:
10708517 - 财政年份:2023
- 资助金额:
$ 51.42万 - 项目类别:
A Novel Large Animal Model for Studying the Developmental Potential and Function of LGR5 Stem Cells in Vivo and in Vitro
用于研究 LGR5 干细胞体内外发育潜力和功能的新型大型动物模型
- 批准号:
10575566 - 财政年份:2023
- 资助金额:
$ 51.42万 - 项目类别:
Elucidating the pathogenesis of a novel animal model mimicking chronic entrapment neuropathy
阐明模拟慢性卡压性神经病的新型动物模型的发病机制
- 批准号:
23K15696 - 财政年份:2023
- 资助金额:
$ 51.42万 - 项目类别:
Grant-in-Aid for Early-Career Scientists
The effect of anti-oxidant on swallowing function in an animal model of dysphagia
抗氧化剂对吞咽困难动物模型吞咽功能的影响
- 批准号:
23K15867 - 财政年份:2023
- 资助金额:
$ 51.42万 - 项目类别:
Grant-in-Aid for Early-Career Scientists