Metabolic determinants of Mtb virulence, vulnerability and variation
结核分枝杆菌毒力、脆弱性和变异的代谢决定因素
基本信息
- 批准号:10438911
- 负责人:
- 金额:$ 257.81万
- 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:2021-07-01 至 2026-04-30
- 项目状态:未结题
- 来源:
- 关键词:Advanced DevelopmentAerosolsAnabolismAntibioticsBacteriaBiologicalBiological AssayBiological MarkersBiologyBloodCRISPR interferenceCharacteristicsChemicalsClinicalComplexDNA-Directed RNA PolymeraseDetectionDevelopmentDiagnosticDiagnostic testsDiseaseDrug RegulationsDrug resistance in tuberculosisElementsEthambutolExhalationFoundationsGenesGeneticGenomicsGenus MycobacteriumGrowthHumanHydrophobicityImmune responseKnowledgeLecithinLinkLipidsMapsMass Spectrum AnalysisMediatingMembraneMembrane LipidsMetabolicModelingMusMycobacterium tuberculosisOrganismPathologicPatientsPenetrationPeptidoglycanPerformancePharmaceutical PreparationsPharmacotherapyPhenotypePhysiologyPlasmaPolymersPolysaccharidesPrevalenceRapid diagnosticsResearchResistanceRifampinRoleSamplingScientistSerumSiteSouth AfricaSpecies SpecificitySphingomyelinsSputumStructureSurfaceSynthesis ChemistrySystemTechnologyTherapeuticTimeTuberculosisUrineVariantVirulenceVirulentWhole Organismactive controlarabinofuranosebasecell envelopechemical propertyclinically relevantcomparativediagnostic strategydrug actiondrug testingdrug-sensitivegene synthesisgenome wide association studygenome-widein vivo Modelinterdisciplinary approachlipid biosynthesislipidomicsmetabolic profilemetabolomicsmouse modelmycobacterialmycolateoverexpressionpandemic diseasepathogenpatient populationpoint-of-care diagnosticsresponseresponse biomarkertooltreatment responseurinary
项目摘要
ABSTRACT - Metabolic determinants of Mtb virulence, vulnerability and variation
Mycobacterium tuberculosis (Mtb) has emerged as the world's most deadly pathogen based in large part on
the highly unusual biological and chemical properties of its cell envelope. Comprised of a distinctive
hydrophobic outer mycolate membrane, anchored to an underlying complex of polysaccharide and
peptidoglycan polymers, the Mtb envelope serves as both the primary interface with, and barrier to, the human
host. In human tuberculosis (TB) disease the Mtb envelope mediates a years-long standoff, and serves as the
barrier to all anti-mycobacterial drugs. Yet, knowledge of its native composition, variation and regulation of
drug entry remains fragmentary. This team of applicants has created new genetic and metabolomic tools to
comprehensively dissect and analyze the metabolite and lipid components of the Mtb envelope on an
organism-wide basis across a large set of clinical isolates. Moreover, this TBRU proposes to provide the first
descriptions of cell envelope variation among isolates from human patients and identify key determinants of its
virulence and barrier to drug action that could inform the development of better diagnostics and therapeutics.
Structures of new molecules will first be determined using synthetic chemistry and mass spectrometry. The
genes encoding these metabolites will then be identified and functionally validated using new genome-scale
CRISPR interference technologies, assays for penetration into the cell envelope, and genetically defined
mouse models of in vivo growth. Using mass spectrometry, we will solve the structures of up to 250 surface
barrier lipids and more than 41 gene-lipid pairs that dominate in cell envelope variation among patients.
Patient-derived Mtb strains will be obtained from clinical samples collected at our field sites in Masiphumelele,
South Africa, where we will implement clinically relevant technology for detection of live Mtb in exhaled (non-
coughed) human bioaerosols. Studies of barrier function place special emphasis on rifampicin as a model
compound due to its clinical importance as a frontline drug and role as a defining element of drug resistant TB.
The ability to analyze patient urine and serum has further resulted in the discovery of new biomarkers of
disease activity and response to drug therapy, motivating linked translational efforts to advance the
development of non-sputum based, real time point-of-care diagnostic tests. This highly interactive group of
scientists thus seeks to provide better drugs and diagnostic tests, as well as a deep and durable scientific
foundation for understanding of the Mtb envelope, especially the particular genes and molecules that control
active remodeling, drug action and human host response.
结核分枝杆菌毒力、易感性和变异的代谢决定因素
项目成果
期刊论文数量(0)
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{{ truncateString('DAVID Branch MOODY', 18)}}的其他基金
Chemical Biological Discovery of Lipid Virulence Factors in the Major Bacterial Pathogens
主要细菌病原体中脂质毒力因子的化学生物学发现
- 批准号:
10518252 - 财政年份:2022
- 资助金额:
$ 257.81万 - 项目类别:
Chemical Biological Discovery of Lipid Virulence Factors in the Major Bacterial Pathogens
主要细菌病原体中脂质毒力因子的化学生物学发现
- 批准号:
10651853 - 财政年份:2022
- 资助金额:
$ 257.81万 - 项目类别:
Study of M. tuberculosis under human host selection to identify virulence and barrier lipids (Project 1)
研究人类宿主选择下的结核分枝杆菌以确定毒力和屏障脂质(项目 1)
- 批准号:
10612035 - 财政年份:2021
- 资助金额:
$ 257.81万 - 项目类别:
Metabolic adaptions of Mycobacterium tuberculosis at diverse host-pathogen interfaces
结核分枝杆菌在不同宿主-病原体界面的代谢适应
- 批准号:
10630740 - 财政年份:2021
- 资助金额:
$ 257.81万 - 项目类别:
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