Metal Binding to the Bacterial Cell Wall
金属与细菌细胞壁的结合
基本信息
- 批准号:7769680
- 负责人:
- 金额:$ 22.67万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2010
- 资助国家:美国
- 起止时间:2010-05-15 至 2015-04-30
- 项目状态:已结题
- 来源:
- 关键词:AbbreviationsAcetylglucosamineAddressAdsorptionAlanineAmidesAmino AcidsAntibiotic TherapyAntibioticsArchitectureAreaBacillus (bacterium)Bacillus anthracisBacteriaBindingBiochemicalBiochemistryBiologyCadmiumCell WallCellsChemicalsChemistryComplexCoupledCytolysisDataDevelopmentDialysis procedureDivalent CationsDrug DesignEnvironmentEquilibriumFacultyFoundationsGeneticGenus staphylococcusGoalsGram-Positive BacteriaHealthHomeostasisHumanIonsKineticsKnowledgeLabelLipidsMeasurementMeasuresMechanicsMediatingMembraneMetal Ion BindingMetalsMethodsMicrobiologyModelingMolecular ModelsMolecular StructureNMR SpectroscopyOutcomePeptidoglycanPhysiologicalPolyaminesPolymersPublic HealthResearchResolutionResourcesRiceRoleSamplingSeriesSiteSolventsSpectrum AnalysisStaphylococcus aureusStructureSystemTechnologyTeichoic AcidsTrainingTranslatingVertebral columnVirulenceWaterWorkabsorptionantimicrobialbasecadmium ionchelationcomputational chemistrycrosslinkdrug developmentextracellularfunctional groupinnovationinorganic phosphateinsightmembermolecular dynamicsmolecular modelingmutantnovelpathogenpathogenic bacteriapolyglycerolpolyribitol phosphateprogramspublic health relevancequantumresearch studysolid statesolid state nuclear magnetic resonancestructural biologyuptake
项目摘要
DESCRIPTION (provided by applicant):
Binding of metals to the bacterial cell wall is essential for peptidoglycan integrity and metal ion homeostasis. Although a potential antibiotic target, drug development suffers from insufficient understanding of how metal binding occurs. The peptidoglycan (PG) and teichoic acids (TA) work in harmony to form the metal binding pocket. Our long-term goal is to provide chemistry and biochemistry explanations of TA function in its different physiological roles. The objective of this application is to determine these rules with regard to metal ion binding in cell walls composed of TA and A13 or A31 PG. These form the sacculus for pathogens B. anthracis and S. aureus, respectively. The central hypothesis of this application is that the metal binding mechanism is mediated through solvent-separated ion-pairs with anionic groups and/or amide carbonyls of PG and the TA polymer. This hypothesis arises from Preliminary NMR Data used to measure the 111Cd2+ to TA distance, which is long enough to allow water molecules to separate these species. Likewise, NMR data show that the phosphate to D-Ala distance is 4.5 ¿ and increases to 5.4 ¿ when Mg2+ is present. Molecular modeling of this distance constraint yields a solvent-separated zwitterion pair. This result contradicts the current paradigm of TA in metal binding, where D-Ala and phosphate supposedly form a contact ion pair and inhibit the chelation of mono and divalent cations. Additional NMR data show that metal binding brings the TA polymer closer the D-Ala group of the PG. This is the first measurement of the TA/PG architecture. Preliminary data guide the development of two specific aims: 1) Identify Changes in TA Structure Upon Metal Chelation; and 2) Characterize the Cell Wall (TA and PG) Structure Before and After Metal Adsorption. The approach uses equilibrium dialysis of Cd2+, Mg2+, Ca2+, K+, and Na+ with cell wall (PG+TA), PG only, and TA only. The concentration of free ions is measured with atomic absorption spectroscopy, providing kinetic data for the equilibrium binding constants. This functional data provides mechanistic insight to the structural data collected with REDOR NMR spectroscopy. Here, 13C and 15N isotopic labeling of the TA and PG components enables REDOR NMR to measure the internuclear distances. Molecular models of localized structure are created with ab-initio calculations with the NMR-based distance constraints. Molecular dynamics simulations using the TA/PG interactions generate models of the cell wall architecture. The innovation of this work arises because it capitalizes on advances in NMR spectroscopy, genetic mutants, and isotopic labeling to solve a complex biochemical problem. Metal binding in the cell wall is an under-investigated, complex, and biologically important system where solid-state NMR experiments could make a truly high impact and yield high-resolution structural information. The proposed research is significant because solid-state NMR methods are coupled with quantum mechanical calculations to elucidate the interactions between teichoic acid, metals, and peptidoglycan. If successful, these studies could potentially guide the development of novel antibiotics.
PUBLIC HEALTH RELEVANCE:
Alleviating harmful effects of bacteria on human health requires precise knowledge of bacterial biochemistry. Solid-state NMR methods are ideally suited to address the metal binding mechanism. Our data can explain metal binding differences between B. anthracis and S. aureus pathogens. After the biochemical mechanisms are known, metal chelation can be blocked with antibiotic therapies.
描述(由申请人提供):
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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Charles V Rice其他文献
Charles V Rice的其他文献
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{{ truncateString('Charles V Rice', 18)}}的其他基金
Universal Anti-PAMP Agent to Improve Wound Healing
促进伤口愈合的通用抗 PAMP 剂
- 批准号:
10647897 - 财政年份:2022
- 资助金额:
$ 22.67万 - 项目类别:
Universal Anti-PAMP Agent to Improve Wound Healing
促进伤口愈合的通用抗 PAMP 剂
- 批准号:
10527023 - 财政年份:2022
- 资助金额:
$ 22.67万 - 项目类别:
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