Investigating Novel Methods to Combat Urinary Tract Infections
研究对抗尿路感染的新方法
基本信息
- 批准号:10705027
- 负责人:
- 金额:$ 12.5万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-09-16 至 2024-09-15
- 项目状态:已结题
- 来源:
- 关键词:AdhesionsAdhesivesAntibiotic ResistanceAntibioticsAntibodiesBacteriaBacterial AdhesinsBacterial AdhesionBacterial Antibiotic ResistanceBacterial InfectionsBenignBindingBinding SitesBiochemicalBiological AssayBiophysicsBladderCathetersCellsChildComplexCystDataDeuteriumDrug DesignDrug TargetingEpithelial CellsEpitopesEscherichia coliExtended-spectrum β-lactamaseGlycoproteinsGoalsHairHydrogenImmunocompromised HostInfectionKlebsiella pneumoniaeKnowledgeLengthMannoseMapsMass Spectrum AnalysisMediatingMeningitisMethodsMolecular ConformationMonoclonal AntibodiesMonoclonal Antibody TherapyMultiple Bacterial Drug ResistanceMutagenesisNMR SpectroscopyPeptide antibodiesPeptidesPlayPositioning AttributePropertyProtein ConformationProteinsReagentResearchResearch PersonnelResearch ProposalsRoentgen RaysRoleSepsisStructureSurfaceSymptomsTestingUrinary tractUrinary tract infectionalternative treatmentcarbapenem resistancecombatcostdesigndiabetic patientinhibiting antibodyinhibitorinsightkidney infectionmutation screeningnovelnovel strategiesolder patientpathogenpathogenic bacteriapreventprogramsreceptorresistant Klebsiella pneumoniaevaccine development
项目摘要
PROJECT SUMMARY/ABSTRACT
Urinary Tract Infections (UTIs) are common in children, the elderly, diabetics, and immunocompromised
patients. UTIs have become difficult to treat due to the rise in multi-drug resistant bacteria such as the
extended spectrum beta lactamase (ESBL) producing Escherichia coli and the carbapenem resistant Klebsiella
pneumoniae. Therefore, there is an urgent need to develop alternative treatments, for instance, anti-adhesive
molecules that block bacteria adhesion to host cells, the all important first step in initiating an infection.
Pathogenic bacteria, like E. coli and K. pneumoniae establish infections in the urinary tract by adhering to host
epithelial cells via adhesion proteins, such as FimH, FmlH and MrkD. The long-term objective of this
proposal is to develop novel methods of inhibiting bacterial adhesion. A monoclonal antibody (mAb) that
inhibits FimH-mediated bacterial adhesion has been discovered, but its mechanism of action has not been
investigated. Moreover, previous studies show that this mAb is neither a competitive nor an allosteric inhibitor,
indicating a novel mechanism of biomolecular inhibition. The aim of this proposal is to elucidate the mechanism
by which the mAb inhibits FimH-mediated bacterial adhesion and develop molecules capable of inhibiting FimH
function. Aim 1 studies will investigate the mechanism of mAb inhibition by mapping the binding site of
the mAb on FimH using Nuclear Magnetic Resonance Spectroscopy (NMR) and Hydrogen Deuterium
Exchange Mass Spectrometry (HDX-MS) and determining the X-ray crystal structure of the FimH-mAb
complex. Furthermore, NMR and HDX-MS will provide information on how mAb binding alters the
conformational dynamics of FimH. These structural and dynamics studies will provide insights into the mAb
mechanism of action. In Aim 2, peptides of the mAb that interact with FimH will be identified using HDX-
MS and tested for binding and inhibitory function in bacterial adhesion assays. The binding and inhibitory
function of the mAb peptides will be optimized using Deep Mutational Scanning (DMS) and Rosetta
computational peptide design. In Aim 3, the structures, and dynamics of FmlH and MrkD will be
investigated, and peptide inhibitors will be developed. Mutagenesis and NMR studies will be carried out to
investigate the different structural conformations and dynamics of FmlH and MrkD. Finally, computational
peptide design using Rosetta will be employed in the de novo design of peptide inhibitors against FmlH and
MrkD.
项目总结/摘要
尿路感染(UTI)常见于儿童、老年人、糖尿病患者和免疫功能低下者。
患者由于多药耐药细菌的增加,UTI变得难以治疗,
产超广谱β-内酰胺酶大肠埃希菌和碳青霉烯类耐药克雷伯菌
肺炎。因此,迫切需要开发替代治疗方法,例如,防粘剂
这些分子可以阻止细菌粘附到宿主细胞上,而粘附是感染开始的重要第一步。
病原菌如E.埃希菌和肺炎通过粘附于宿主而在泌尿道中建立感染
上皮细胞通过粘附蛋白如FimH、FmlH和MrkD。长期目标是
建议开发抑制细菌粘附的新方法。一种单克隆抗体(mAb),
抑制FimH介导的细菌粘附已经被发现,但其作用机制尚未被阐明。
研究了此外,先前的研究表明,这种mAb既不是竞争性的也不是变构抑制剂,
这表明了一种新的生物分子抑制机制。本提案的目的是阐明
通过该方法,mAb抑制FimH介导的细菌粘附并产生能够抑制FimH的分子
功能目的1研究通过定位单克隆抗体的结合位点来研究单克隆抗体抑制的机制。
使用核磁共振光谱法(NMR)和氢氘分析FimH上的mAb
交换质谱法(HDX-MS)和测定FimH-mAb的X射线晶体结构
复杂.此外,NMR和HDX-MS将提供关于mAb结合如何改变
FimH的构象动力学这些结构和动力学研究将提供对mAb的深入了解,
作用机制。在目的2中,将使用HDX-2000鉴定与FimH相互作用的mAb的肽。
MS并在细菌粘附测定中测试结合和抑制功能。结合和抑制
将使用深度突变扫描(DMS)和Rosetta优化mAb肽的功能
计算肽设计在目标3中,FmlH和MrkD的结构和动力学将是
研究,并将开发肽抑制剂。将进行诱变和核磁共振研究,
研究FmlH和MrkD的不同结构构象和动力学。最后,计算
使用Rosetta的肽设计将用于从头设计针对FmlH的肽抑制剂,
D先生
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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PEARL MAGALA其他文献
PEARL MAGALA的其他文献
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{{ truncateString('PEARL MAGALA', 18)}}的其他基金
Investigating Novel Methods to Combat Urinary Tract Infections
研究对抗尿路感染的新方法
- 批准号:
10369290 - 财政年份:2022
- 资助金额:
$ 12.5万 - 项目类别:
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