Novel antimicrobials targeting type IV pilus and type 2 secretion systems
针对 IV 型菌毛和 2 型分泌系统的新型抗菌药物
基本信息
- 批准号:9089860
- 负责人:
- 金额:$ 4.57万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2015
- 资助国家:美国
- 起止时间:2015-07-01 至 2016-10-31
- 项目状态:已结题
- 来源:
- 关键词:AcinetobacterAcinetobacter baumanniiActive SitesAdherenceAnimal ModelAntibiotic ResistanceAntibioticsAntimicrobial ResistanceAspartic AcidBacteriaBacterial InfectionsBindingBiogenesisBiological AssayCharacteristicsChemicalsChimeric ProteinsComplexDiseaseDrug TargetingDsRedEnergy TransferEnzymesEquipmentEscherichia coliFimbriae ProteinsFluorescenceFluorescence AnisotropyFluorescence PolarizationFormulationFosteringGoalsGrowthHealthHumanImmunoblottingIn VitroInfectionLeadLibrariesMarylandMedicineMembraneModelingMolecular MachinesMolecular ModelsMutationN-terminalNeisseria gonorrhoeaeOrganismPathogenesisPeptide HydrolasesPeptide Signal SequencesPerformancePharmaceutical ChemistryPhasePhysiciansPilumPneumoniaPreclinical Drug EvaluationPreclinical TestingPreventionProbabilityPropertyProtease InhibitorProteinsPseudomonas aeruginosaPseudomonas aeruginosa pneumoniaQuality ControlRecombinant ProteinsResistanceResourcesSeriesSpecificityStructureSurfaceSystemTestingTherapeuticToxinUniversitiesValidationVirulenceanalogantimicrobialantimicrobial drugappendagedrug developmentdrug discoveryefficacy testingenteropathogenic Escherichia coliexperienceimprovedin vitro activityin vivoinhibitor/antagonistinnovationkillingsmolecular modelingmouse modelmutantnovelnovel therapeuticspathogenpreventprotein S precursorscreeningsmall moleculesuccesstherapeutic target
项目摘要
DESCRIPTION (provided by applicant): Bacterial pathogens have conserved complex molecular machines that are required to cause disease. Among these machines are those that make up a type IV pilus (T4P) biogenesis apparatus and the related type II secretion (T2S) machine. T4Ps are surface appendages essential for adherence and host colonization by many important bacterial pathogens; T2S systems export toxins that are critical for many diseases. Acinetobacter baumanii, Pseudomonas aeruginosa, and Neisseria gonorrhoeae all produce T4Ps. Among the components common to both machines is a pre-pilin peptidase enzyme that specifically removes the characteristic N-terminal signal sequence from pre-pilin proteins and N-methylates the nascent amino terminus. These enzymes are highly conserved, absolutely required for T4P and T2S function, and represent a novel class of neutral pH aspartic acid peptidases that do not resemble mammalian enzymes. As such, they are ideal targets for new drug discovery. We have devised an in vivo Föster resonance energy transfer (FRET) system comprised of three recombinant proteins expressed in E. coli: the pre-pilin peptidase, the pre-pilin protein fused to enhanced yellow fluorescent protein (eYFP), and an essential assembly protein to which the pre-pilin binds fused to dsRed. Cleavage of the pre-pilin fusion protein by the pre-pilin peptidase releases eYFP and prevents FRET with dsRed. If the pre-pilin peptidase is inactivated by mutation, then FRET occurs. We will adapt this extremely sensitive system and a related even simpler system that relies on fluorescence anisotropy to develop in vitro high-throughput small molecule screens to identify pre-pilin peptidase inhibitor candidates. Secondary assays will establish specificity and spectrum of activity. The initial effort will provie candidates that will subsequently subjected to further chemical refinement to enhance potency, specificity and activity against whole bacteria. Finally, (a) lead compound(s) will be advanced to preclinical testing using an established murine model of P. aeruginosa pneumonia in which T4Ps are required for disease. Ultimately, the goal is to discover an entirely novel therapeutic class of anti-virulence agents to improve human health.
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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MICHAEL S DONNENBERG其他文献
MICHAEL S DONNENBERG的其他文献
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{{ truncateString('MICHAEL S DONNENBERG', 18)}}的其他基金
Novel antimicrobials targeting type IV pilus and type 2 secretion systems
针对 IV 型菌毛和 2 型分泌系统的新型抗菌药物
- 批准号:
8955922 - 财政年份:2015
- 资助金额:
$ 4.57万 - 项目类别:
Novel antimicrobials targeting type IV pilus and type 2 secretion systems
针对 IV 型菌毛和 2 型分泌系统的新型抗菌药物
- 批准号:
9386954 - 财政年份:2015
- 资助金额:
$ 4.57万 - 项目类别:
Structure and Role in Disease of Clostridium difficile Type IV Pili
艰难梭菌 IV 型菌毛的结构和在疾病中的作用
- 批准号:
8504227 - 财政年份:2013
- 资助金额:
$ 4.57万 - 项目类别:
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