Structure-based targeting of the C. difficile toxin (CDT) from hypervirulent bacterial strains
基于结构的高毒力细菌菌株中艰难梭菌毒素 (CDT) 的靶向
基本信息
- 批准号:10455150
- 负责人:
- 金额:$ 52.18万
- 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:2021-08-06 至 2023-07-31
- 项目状态:已结题
- 来源:
- 关键词:3-DimensionalAddressAdenosine Diphosphate RiboseAmino AcidsAnisotropyAntibioticsAreaBacteriaBacterial InfectionsBindingBiological AssayCD44 geneCellsChemicalsClassificationClostridium difficileColonoscopyComplexComputer softwareCorynebacterium diphtheriaeCryoelectron MicroscopyCytoplasmDangerousnessDataData AnalysesDetectionDevelopmentDiarrheaDiphtheria ToxinEnterotoxinsEnzymesFutureG ActinGenerationsGoalsGoldHealthcareInfectionJournalsLaboratoriesLengthMeasuresMedicalMembraneMethodsModelingModificationMolecularMutationPeer ReviewPharmaceutical PreparationsPhysiologicalPreparationProcessProteinsPseudomonas aeruginosaPublicationsReceptor CellRecurrenceReportingResearchResolutionRoentgen RaysSiteSite-Directed MutagenesisStructureSystemTargeted ToxinsTherapeuticToxic effectToxinValidationWorkX-Ray Crystallographybasebiophysical propertiescytolethal distending toxincytotoxicdensitydrug developmentdrug discoveryexperimental studyfecal transplantationinstrumentationinterestmutantprogramsprotein structurepublic health prioritiesreceptorreceptor bindingresponsestructural biologytherapeutic targettreatment strategy
项目摘要
Abstract – Targeting Clostridium difficile infection (CDI) is challenging because treatments are limited to a
small number of antibiotics, colonoscopy, and experimental methods (i.e. fecal transplant), and there are
unacceptably high recurrence rates, particularly with hypervirulent strains such as NAP1/P1/027. One serious
problem with hypervirulent strains is that they have a binary toxin termed the C. difficile toxin (CDT), in addition
to the enterotoxins TsdA and TsdB. The CDT binary toxin has an enzymatic component, termed CDTa, and a
pore-forming or delivery subunit termed CDTb. The cytotoxic response to host cells is the result of a catalytic
transfer of the ADP-ribose moiety of NAD to host G-actin, its physiological substrate, via CDTa. Delivery of
CDTa to the cytoplasm is via the pore-forming component of the binary toxin, CDTb. While treatment options
exist for TcdA/TcdB, there is no therapy to target CDT and the mechanism of action for the CDTa/CDTb binary
toxin associated with the hypervirulent strains of CDI is not well understood. In our labs, a structural biology
approach is underway via cryoEM to characterize the CDTa/CDTb binary complex using active and fully
processed full-length constructs of both CDTa and CDTb (Aim 1). This will be followed by more detailed
structural and dynamic studies involving specific domains of the binary toxins using NMR and X-ray
crystallography (Aim 1). In Aim 2, studies of complexes relevant to host cell engagement are planned to
include those of CDTb and the CDTa/CDTb complex in membrane-like media and bound to constructs derived
from host cell receptors (i.e. CD44, LSR). Together the structures will be used to define regions on CDT
important for engaging the host cell and provide information necessary to block this process, as a therapeutic
approach. Because other infectious bacteria make use of similar “Type III” systems for delivering ADP-
ribosylating toxins (i.e. Corynebacterium diphtheriae, diphtheria toxin, Pseudomonas aeruginosa, and others),
it is anticipated that the research completed here for CDI could benefit treatment strategies for hypervirulent C.
difficile as well as for other dangerous bacterial infections.
针对艰难梭菌感染(CDI)是具有挑战性的,因为治疗仅限于a
项目成果
期刊论文数量(4)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
The Importance of Therapeutically Targeting the Binary Toxin from Clostridioides difficile.
- DOI:10.3390/ijms22062926
- 发表时间:2021-03-13
- 期刊:
- 影响因子:5.6
- 作者:Abeyawardhane DL;Godoy-Ruiz R;Adipietro KA;Varney KM;Rustandi RR;Pozharski E;Weber DJ
- 通讯作者:Weber DJ
Computer-Aided Drug Design: An Update.
- DOI:10.1007/978-1-0716-2855-3_7
- 发表时间:2023
- 期刊:
- 影响因子:0
- 作者:Wenbo Yu;David J. Weber;Alexander D. MacKerell
- 通讯作者:Wenbo Yu;David J. Weber;Alexander D. MacKerell
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David Joseph Weber其他文献
David Joseph Weber的其他文献
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{{ truncateString('David Joseph Weber', 18)}}的其他基金
Signal Propagation in Protein Allostery: Mechanism and Evolution
蛋白质变构中的信号传播:机制和进化
- 批准号:
10326378 - 财政年份:2019
- 资助金额:
$ 52.18万 - 项目类别:
950 MHz NMR Spectrometer with Cryogenic Probe
带低温探头的 950 MHz NMR 波谱仪
- 批准号:
7839937 - 财政年份:2010
- 资助金额:
$ 52.18万 - 项目类别:
Restoration of Tumor Suppression Activity in Malignant Melanoma
恶性黑色素瘤肿瘤抑制活性的恢复
- 批准号:
7812305 - 财政年份:2009
- 资助金额:
$ 52.18万 - 项目类别:
Restoration of Tumor Suppression Activity in Malignant Melanoma
恶性黑色素瘤肿瘤抑制活性的恢复
- 批准号:
7250875 - 财政年份:2006
- 资助金额:
$ 52.18万 - 项目类别:
Restoration of Tumor Suppression Activity in Malignant Melanoma
恶性黑色素瘤肿瘤抑制活性的恢复
- 批准号:
8188169 - 财政年份:2006
- 资助金额:
$ 52.18万 - 项目类别:
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