Structural Determinants of Permeation Barriers in Escherichia coli
大肠杆菌渗透屏障的结构决定因素
基本信息
- 批准号:10749251
- 负责人:
- 金额:$ 62.32万
- 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:2023-05-31 至 2028-04-30
- 项目状态:未结题
- 来源:
- 关键词:3-DimensionalAcademiaAgreementAlkynesAntibiotic TherapyAntibioticsAzidesBacteriaBinding SitesBiochemicalBiological AssayBiologyCellsChemicalsCollectionCommunitiesCytoplasmDataData SetDrug TargetingEpitopesEscherichia coliFluorescenceFoundationsGenomicsGram-Negative BacteriaHealthcareIndustryKnock-inKnock-outLabelLaboratoriesLibrariesMeasurableMeasuresMedicalMembraneMetabolicMethodologyMethodsModernizationMolecularOperative Surgical ProceduresOrganellesOrganic SynthesisPenetrationPermeabilityPharmaceutical ChemistryPharmaceutical PreparationsPhasePhysical condensationPredispositionProteomicsReactionReagentResearchResolutionScienceSpecificityTestingThree-Dimensional ImagingVDAC1 geneWorkcell envelopecheminformaticscycloadditiondesigndrug discoveryefflux pumpfluorophorehigh throughput analysishuman diseaseinfection riskinnovationinstrumentationmachine learning algorithmmetabolomicsminimal risknovelpathogenperiplasmscreeningsmall moleculesmall molecule librariesstructural determinantssubcellular targetingtoolultra high resolution
项目摘要
PROJECT SUMMARY
Antibiotics represent the most successful class of drugs developed by modern science. They have spurred
numerous medical advances by facilitating invasive surgeries with minimal risk of infection. Today, a major
healthcare crisis looms as we are fast approaching a post-antibiotic era. Historically, it has proven to be much
more difficult to find agents that are active against Gram-negative pathogens compared to Gram-positive
pathogens. The primary reason is that Gram-negative bacteria have a unique asymmetric outer membrane (OM)
in addition to an inner membrane. The targets for most antibiotics reside beyond the OM, and thus these
molecules need to penetrate the OM to be active. Yet, the OM is uniquely effective in blocking the translocation
of small molecules, thus creating a major challenge for the field.
The Golden Era of antibiotics leveraged naturally abundant small molecules that were readily identified using
traditional methods; however, this methodology has proven to be much more difficult to be further mined for new
antibiotics during the past several decades. The next phase of antibiotic drug discovery has the potential to be
supported by our increasing collection of proteomics, genomics, and metabolomics data that will reveal promising
drug targets. Academia and industry could potentially exploit these data sets to design small molecule agents
that are potent and of high specificity. To accomplish this, the field fundamentally requires guiding principles
describing the molecular determinants of permeation into bacterial cells akin to the Lipinski’s rules of 5 (Ro5).
We propose to develop a novel fluorescence assay that measures the accumulation of small molecules in Gram-
negative pathogens based on a combination of HaloTag expression and anchoring of a biorthogonal epitope
within HaloTag. Our team will systematically (testing established antibiotics with known permeation profiles) and
broadly (screening a unique library of small molecules modified with an azide tag) apply this approach to
measurably grow our fundamental understanding of the molecular determinants of permeation. Additionally, we
will utilize the same platform to provide unprecedented spatial resolution of the distribution of small molecules
(including known antibiotics) in subcellular compartments.
项目摘要
抗生素是现代科学开发的最成功的一类药物。他们刺激了
许多医疗进步,促进侵入性手术,感染风险最小。今天,一位少校
随着我们迅速进入后抗生素时代,医疗保健危机迫在眉睫。从历史上看,
与革兰氏阳性病原体相比,更难找到对革兰氏阴性病原体有活性的试剂
病原体主要原因是革兰氏阴性菌具有独特的不对称外膜(OM)
除了内膜之外。大多数抗生素的靶标位于OM之外,因此这些
分子需要穿透有机质才能活跃然而,OM是唯一有效地阻止易位
小分子,从而为该领域带来了重大挑战。
抗生素的黄金时代利用了天然丰富的小分子,这些小分子很容易通过使用
传统的方法;然而,这种方法已被证明是更难以进一步挖掘新的
抗生素在过去的几十年里抗生素药物发现的下一阶段有可能是
我们越来越多地收集蛋白质组学、基因组学和代谢组学数据,
药物靶点学术界和工业界可能会利用这些数据集来设计小分子药物
它们是有效的并且具有高度特异性。要做到这一点,该领域从根本上需要指导原则
描述了渗透到细菌细胞中的分子决定因素,类似于Lipinski规则5(Ro 5)。
我们建议开发一种新的荧光测定法,测量革兰氏阴性杆菌中小分子的积累,
基于HaloTag表达和双正交表位锚定的组合的阴性病原体
在HaloTag中。我们的团队将系统地(测试具有已知渗透特性的已确立抗生素)和
广泛地(筛选用叠氮化物标签修饰的小分子的独特文库)将该方法应用于
可测量地增长我们对渗透的分子决定因素的基本理解。另外我们
将利用相同的平台提供前所未有的小分子分布的空间分辨率
(包括已知的抗生素)在亚细胞区室。
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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Marcos M. Pires其他文献
emNeisseria gonorrhoeae/em scavenges host sialic acid for Siglec-mediated, complement-independent suppression of neutrophil activation
淋病奈瑟菌(Neisseria gonorrhoeae)清除宿主唾液酸以进行 Siglec 介导的、补体非依赖性的中性粒细胞活化抑制
- DOI:
10.1128/mbio.00119-24 - 发表时间:
2024-03-29 - 期刊:
- 影响因子:4.700
- 作者:
Amaris J. Cardenas;Keena S. Thomas;Mary W. Broden;Noel J. Ferraro;Marcos M. Pires;Constance M. John;Gary A. Jarvis;Alison K. Criss - 通讯作者:
Alison K. Criss
Genetic Determinants of Surface Accessibility in emStaphylococcus aureus/em
金黄色葡萄球菌表面可及性的遗传决定因素
- DOI:
10.1021/acs.bioconjchem.2c00173 - 发表时间:
2022-05-18 - 期刊:
- 影响因子:3.900
- 作者:
Noel J. Ferraro;Marcos M. Pires - 通讯作者:
Marcos M. Pires
Marcos M. Pires的其他文献
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{{ truncateString('Marcos M. Pires', 18)}}的其他基金
Bacterial and Molecular Determinants of Mycobacterial Impermeability
分枝杆菌不渗透性的细菌和分子决定因素
- 批准号:
10749613 - 财政年份:2023
- 资助金额:
$ 62.32万 - 项目类别:
Chemical Remodeling of Cell Surface to Enhance the Accumulation of Therapeutic Bacteria to Tumors
细胞表面的化学重塑以增强治疗性细菌对肿瘤的积累
- 批准号:
10535464 - 财政年份:2022
- 资助金额:
$ 62.32万 - 项目类别:
Chemical Remodeling of Cell Surface to Enhance the Accumulation of Therapeutic Bacteria to Tumors
细胞表面的化学重塑以增强治疗性细菌对肿瘤的积累
- 批准号:
10391986 - 财政年份:2022
- 资助金额:
$ 62.32万 - 项目类别:
Unraveling Bacterial Cell Wall Biosynthesis and Sensing via Synthetic Analogs
通过合成类似物解开细菌细胞壁的生物合成和传感
- 批准号:
10381814 - 财政年份:2017
- 资助金额:
$ 62.32万 - 项目类别:
Unraveling Bacterial Cell Wall Biosynthesis and Sensing via Synthetic Analogs
通过合成类似物解开细菌细胞壁的生物合成和传感
- 批准号:
9382168 - 财政年份:2017
- 资助金额:
$ 62.32万 - 项目类别:
Unraveling Bacterial Cell Wall Biosynthesis and Sensing via Synthetic Analogs
通过合成类似物解开细菌细胞壁的生物合成和传感
- 批准号:
10552391 - 财政年份:2017
- 资助金额:
$ 62.32万 - 项目类别:
Unraveling Bacterial Cell Wall Biosynthesis and Sensing via Synthetic Analogs
通过合成类似物解开细菌细胞壁的生物合成和传感
- 批准号:
10242123 - 财政年份:2017
- 资助金额:
$ 62.32万 - 项目类别:
Unraveling Bacterial Cell Wall Biosynthesis and Sensing via Synthetic Analogs
通过合成类似物解开细菌细胞壁的生物合成和传感
- 批准号:
10112721 - 财政年份:2017
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$ 62.32万 - 项目类别:
Development of a Novel Artificial Diiron Protein with N-hydroxylase Activity
具有 N-羟化酶活性的新型人工二铁蛋白的开发
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8004780 - 财政年份:2010
- 资助金额:
$ 62.32万 - 项目类别:
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