Using Salmonella Pathogenesis and Cell Biology as a Discovery Tool
使用沙门氏菌发病机制和细胞生物学作为发现工具
基本信息
- 批准号:10665946
- 负责人:
- 金额:$ 23.48万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-03-01 至 2025-02-28
- 项目状态:未结题
- 来源:
- 关键词:AddressAnimalsBacteriaBacterial InfectionsBindingBiologicalCRISPR interferenceCell Culture TechniquesCell Membrane PermeabilityCell membraneCellsCellular biologyChemicalsCholesterolColony-forming unitsCytolysisDataDoseEscherichia coliFemaleFutureGenesGeneticGram-Negative BacteriaGrowthInfectionInterruptionIonsLeadLipid BilayersLipidsLiverMacrophageMacrophage Cell BiologyMammalian CellMembraneMembrane ProteinsMethodsMicroscopyModificationMusNatural ImmunityNaturePathogenesisPathogenicityPathway interactionsPeptidesPermeabilityPhagosomesPolymyxin BProcessPropidium DiiodideProteinsProtonsPublishingResistanceSalmonellaSalmonella typhimuriumSpleenTestingToxic effectVesicleVirulenceWorkbiological adaptation to stresscell injuryefflux pumpexperimental studyhigh rewardhigh riskin vivoinhibitorinnovationknock-downmalemutantnanomolarnegative affectnovel strategiespathogensexsmall moleculetooltranscriptomicsvoltage
项目摘要
SUMMARY
The inner membrane of pathogenic Gram-negative bacteria contains lipids and proteins that are distinct from
those of mammalian cell membranes. Inner membranes therefore could be attacked by small molecules during
infection, when soluble host innate immunity damages the protective outer membrane barrier, increasing
access to chemicals. Exploration of molecules that a) interrupt pathogenesis in cell culture with minimal host
cell damage, and b) perturb inner membranes under broth conditions that permeabilize the outer membrane
has the potential to reveal whether bacterial virulence can be short-circuited by compounds that disturb inner
membranes but do not inhibit bacterial growth under standard broth conditions. An in-macrophage cell biology-
based method called SAFIRE appears to identify compounds that negatively affect bacterial inner membranes
while sparing host cell membranes. Within this application we propose to study a SAFIRE-identified compound,
D66, which appears to damage bacterial inner membranes without lysing them. Published and unpublished
preliminary data together indicate that D66 accesses bacterial inner membranes when the LPS layer is
damaged or efflux pumps are compromised, conditions consistent with the macrophage phagosome. However,
D66 disrupts inner membrane voltage rapidly and at concentrations that do not destroy the inner membrane
lipid bilayer, indicating that the compound is not causing bacterial lysis but is disturbing the membrane more
subtly. We hypothesize that D66 damages the bacterial cell membrane in a process that triggers stress
response pathways but does not cause rapid physical disruption of the lipid bilayer. We propose cell biological
and animal infection experiments to test this hypothesis.
总结
致病性革兰氏阴性菌的内膜含有与革兰氏阴性菌不同的脂质和蛋白质。
哺乳动物细胞膜的那些。因此,内膜可能会受到小分子的攻击,
感染,当可溶性宿主先天免疫损害保护性外膜屏障时,
获取化学品。探索a)在具有最小宿主的细胞培养物中中断发病机制的分子
细胞损伤,和B)在肉汤条件下扰动B内膜,使外膜透化
有可能揭示细菌的毒力是否可以被干扰内部代谢的化合物短路。
膜,但在标准肉汤条件下不抑制细菌生长。巨噬细胞内细胞生物学
一种名为SAFIRE的方法似乎可以识别出对细菌内膜产生负面影响的化合物
同时保留宿主细胞膜。在本申请中,我们建议研究一种SAFIRE鉴定的化合物,
D66,它似乎破坏细菌内膜而不溶解它们。已发表和未发表
初步数据共同表明,当LPS层被破坏时,D66进入细菌内膜。
受损或外排泵受损,情况与巨噬细胞吞噬体一致。然而,在这方面,
D66在不破坏内膜的浓度下迅速破坏内膜电压
脂质双层,表明该化合物不会引起细菌溶解,但会更多地干扰膜
很微妙我们假设D66在引发压力的过程中破坏细菌细胞膜
反应途径,但不会导致脂质双层的快速物理破坏。我们提出细胞生物学
和动物感染实验来验证这一假设。
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)
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Corrella S Detweiler其他文献
Corrella S Detweiler的其他文献
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{{ truncateString('Corrella S Detweiler', 18)}}的其他基金
Infection-Dependent Vulnerabilities of Gram-negative Bacterial Pathogens
革兰氏阴性细菌病原体的感染依赖性脆弱性
- 批准号:
10592676 - 财政年份:2023
- 资助金额:
$ 23.48万 - 项目类别:
A Small Molecule That Blocks Salmonella Replication in Macrophages
阻止沙门氏菌在巨噬细胞中复制的小分子
- 批准号:
10312125 - 财政年份:2020
- 资助金额:
$ 23.48万 - 项目类别:
Chemical Probes for Bacteria-Macrophage Interactions
用于细菌-巨噬细胞相互作用的化学探针
- 批准号:
9171993 - 财政年份:2016
- 资助金额:
$ 23.48万 - 项目类别:
Macrophages, Granulomas, and Bacterial Persistence
巨噬细胞、肉芽肿和细菌持久性
- 批准号:
9277403 - 财政年份:2016
- 资助金额:
$ 23.48万 - 项目类别:
A Novel Screen for Antibacterials that Are Non-Toxic to Mammals
一种对哺乳动物无毒的抗菌药物的新型筛选
- 批准号:
9186486 - 财政年份:2015
- 资助金额:
$ 23.48万 - 项目类别:
A Novel Screen for Antibacterials that Are Non-Toxic to Mammals
一种对哺乳动物无毒的抗菌药物的新型筛选
- 批准号:
9015218 - 财政年份:2015
- 资助金额:
$ 23.48万 - 项目类别:
Host Pathways that Enable /Salmonella/ Replication Within Hemophagocytic Macropha
使/沙门氏菌/在噬血细胞巨噬细胞内复制的宿主途径
- 批准号:
8281809 - 财政年份:2012
- 资助金额:
$ 23.48万 - 项目类别:
Host Pathways that Enable /Salmonella/ Replication Within Hemophagocytic Macropha
使/沙门氏菌/在噬血细胞巨噬细胞内复制的宿主途径
- 批准号:
8418684 - 财政年份:2012
- 资助金额:
$ 23.48万 - 项目类别:
Hemophagocytic Macrophages and Systemic Salmonella Infection
噬血细胞巨噬细胞和全身性沙门氏菌感染
- 批准号:
8805824 - 财政年份:2012
- 资助金额:
$ 23.48万 - 项目类别:
Hemophagocytic Macrophages and Systemic Salmonella Infection
噬血细胞巨噬细胞和全身性沙门氏菌感染
- 批准号:
8433309 - 财政年份:2012
- 资助金额:
$ 23.48万 - 项目类别:
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