The role of cardiolipin in the biogenesis of the Gram-negative bacterial cell envelope
心磷脂在革兰氏阴性细菌细胞包膜生物发生中的作用
基本信息
- 批准号:10731444
- 负责人:
- 金额:$ 67.71万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-06-01 至 2028-05-31
- 项目状态:未结题
- 来源:
- 关键词:ATP phosphohydrolaseATP-Binding Cassette TransportersAffinityAntibiotic ResistanceAntibioticsAntimicrobial ResistanceAutomobile DrivingBacteriaBacterial InfectionsBinding SitesBiochemicalBiogenesisBiologyCardiolipinsCell Membrane PermeabilityCell SurvivalCellsCessation of lifeClinicalCytoplasmDataDefectDevelopmentDrug EffluxEncapsulatedEnzymesEquilibriumEscherichia coliFaceFeedbackFutureGenesGeneticGlycerophospholipidsGram-Negative BacteriaGrowthHealthcareHeterogeneityInfectionLibrariesLipid ALipidsLipopolysaccharidesMaintenanceMembraneMembrane LipidsModelingMolecularMulti-Drug ResistanceOrganismPathway interactionsPeptidoglycanPumpRegulationResistanceRoleSideSurfaceSystemTransmembrane Transportantimicrobialcardiolipin synthasecell envelopecombinatorialdensitydesigneconomic costfightingfitnessglobal healthinsightlipidomelipophilicitymembrane biogenesismutantnew therapeutic targetnovelnovel therapeuticspathogenpreventprotein transportstem
项目摘要
Abstract
The increasing rise in antibiotic resistance and the diminished discovery of new antimicrobials threatens global
healthcare. Of particular concern are Gram-negative pathogens, as these organisms are intrinsically resistant
to multiple classes of antibiotics and the discovery of novel drugs targeting these bacteria has remained
challenging. The innate resistance of these organisms is provided primarily by their outer membrane (OM), a
defining feature of Gram negatives that encapsulates their peptidoglycan layer. Unlike the inner membrane
(IM) that is composed solely of glycerophospholipids (GPLs), the OM is asymmetrical with GPLs found in the
inner leaflet and lipopolysaccharide (LPS) localized to the outer leaflet. This unique membrane organization
affords protection from large polar molecules, as well as lipophilic compounds, creating an impervious barrier.
Since the OM is essential, pathways required for its assembly are key targets for antimicrobial design.
Currently, there are no antibiotics that directly target OM biogenesis in clinical use and first attempts have
proven difficult. Thus, it remains critical to investigate cell envelope biology for future and current antimicrobial
design.
Recently, we discovered a connection between the GPL cardiolipin (CL) and the synthesis and transport of
LPS. E. coli harbors three distinct enzymes that synthesize CL, yet CL is not required for cell viability and is the
least abundant of the three major GPLs in Gram negatives. We found LpxM, the enzyme that adds the last acyl
chain to the lipid anchor of LPS, to be critical for viability in the absence of clsA. Suppressors of clsA and lpxM
synthetic lethality were identified in msbA, a gene that encodes the essential, homodimeric ABC transporter
that “flips” LPS across the IM. Multiple pieces of genetic and biochemical data supported a model in which CL
enhances MsbA activity driving LPS transport. Also, we observed that single mutants lacking either ClsA, the
primary CL synthase, or LpxM have reduced LPS levels. This suggests the cell can “sense” defects in LPS
transport at the cytoplasmic face of the IM and slow LPS synthesis to balance OM lipid content. In the current
application we will define (i) the functional role of CL in MsbA-dependent LPS transport, (ii) characterize
specific MsbA-CL interactions and determine how they impact MsbA activity, (iii) determine if ClsA and MsbA
are co-localized in the bacterial cell envelope, and (iv) determine how defects in LPS transport results in
feedback inhibition of LPS synthesis. Completion of these Aims will provide novel insights into cell envelope
biogenesis and promote the development of novel therapeutics targeting Gram-negative pathogens.
摘要
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
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Michael Stephen Trent其他文献
Michael Stephen Trent的其他文献
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{{ truncateString('Michael Stephen Trent', 18)}}的其他基金
Synthesis and transport of outer membrane components across the Gram-negative cell envelope
外膜成分的合成和跨革兰氏阴性细胞包膜的运输
- 批准号:
10680968 - 财政年份:2023
- 资助金额:
$ 67.71万 - 项目类别:
The Cell Envelope of the Multi-Drug Resistant Pathogen Acinetobacter baumannii
多重耐药病原体鲍曼不动杆菌的细胞包膜
- 批准号:
10113527 - 财政年份:2020
- 资助金额:
$ 67.71万 - 项目类别:
The Cell Envelope of the Multi-Drug Resistant Pathogen Acinetobacter baumannii
多重耐药病原体鲍曼不动杆菌的细胞包膜
- 批准号:
10542396 - 财政年份:2020
- 资助金额:
$ 67.71万 - 项目类别:
The Cell Envelope of the Multi-Drug Resistant Pathogen Acinetobacter baumannii
多重耐药病原体鲍曼不动杆菌的细胞包膜
- 批准号:
10328269 - 财政年份:2020
- 资助金额:
$ 67.71万 - 项目类别:
Molecular mechanisms required for the maintenance of the gram-negative outer membrane
维持革兰氏阴性外膜所需的分子机制
- 批准号:
10159193 - 财政年份:2018
- 资助金额:
$ 67.71万 - 项目类别:
Molecular mechanisms required for the maintenance of the gram-negative outer membrane
维持革兰氏阴性外膜所需的分子机制
- 批准号:
10403653 - 财政年份:2018
- 资助金额:
$ 67.71万 - 项目类别:
Molecular mechanisms required for the maintenance of the gram-negative outer membrane
维持革兰氏阴性外膜所需的分子机制
- 批准号:
9917747 - 财政年份:2018
- 资助金额:
$ 67.71万 - 项目类别:
Development of a novel vaccine platform: Surface Antigen/Adjuvant Vaccine Engineering (SAAVE)
新型疫苗平台的开发:表面抗原/佐剂疫苗工程(SAAVE)
- 批准号:
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Rethinking the barrier: How a Gram-negative bacterium alters its surface to become multidrug resistant
重新思考屏障:革兰氏阴性细菌如何改变其表面以产生多重耐药性
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9102680 - 财政年份:2015
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$ 67.71万 - 项目类别:
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