Mechanisms of Resistance in Gram-Negative Bacteria
革兰氏阴性菌的耐药机制
基本信息
- 批准号:8088429
- 负责人:
- 金额:$ 37.88万
- 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:2010-07-26 至 2012-06-30
- 项目状态:已结题
- 来源:
- 关键词:Active SitesAgeAnabolismAntibioticsAntimicrobial Cationic PeptidesAntimicrobial ResistanceBacteriaBacterial InfectionsBiochemicalBreathingCell surfaceChronicClinicalColistinCollaborationsComplexCystic FibrosisDataDrug DesignEnzyme Inhibitor DrugsEnzyme InhibitorsEnzymesEvaluationFamilyGenesGram-Negative BacteriaHydroxymethyltransferasesImmune responseImmune systemIn VitroInfectionInfection preventionInfiltrationLipid ALungMediatingMembraneModificationMolecularMulti-Drug ResistanceMultienzyme ComplexesMutagenesisMutationNatural ImmunityNatureOperonOxidoreductasePalmitatesPathway interactionsPatientsPeptide AntibioticsPharmaceutical PreparationsPolymyxin ResistancePolymyxinsProteinsPseudomonasPseudomonas InfectionsPseudomonas aeruginosaQuality of lifeResistanceSiteStructureTestingVirulenceWorkairway epitheliumairway inflammationaminoarabinoseanalogantimicrobialantimicrobial peptidebacterial resistancebactericidebasecystic fibrosis airway epitheliacystic fibrosis patientsdesignfightingimprovedin vitro Assayinhibitor/antagonistkillingsmortalitypathogenresearch studyresistance mechanismundecaprenyl phosphate
项目摘要
Patients with Cystic Fibrosis (CF) develop chronic airway infections with the
opportunistic gram negative bacteria Pseudomonas aeruginosa. Airway inflammation
and neutrophilic infiltration without bacterial destruction characterize these infections. It
has been shown that Pseudomonas isolated from Cystic Fibrosis patients have specific,
virulence-associated modifications in their lipid A structure. These modifications, which
include substitutions with palmitate and 4-aminoarabinose, are responsible for resistance
to cationic antimicrobial peptides (CAMPs), an important component of innate immunity
and Polymyxin, a CAMP antibiotic. The enzymes responsible for the biosynthesis of 4-
aminoarabinose-lipid A are clustered in an operon recently renamed to ArnBCADTEF.
Mutation of any of these genes abolishes 4-aminoarabinose addition to lipid A and
resistance to CAMPs. Based on our previous structural and biochemical work with ArnA
we have developed a strategy for selective inhibition ArnA . In this proposal we also
target ArnD, a hypothetical deformylase essential for the biosynthesis of 4-
aminoarabinose-lipid A, for biochemical and structural characterization. Inhibition of any
of these enzymes would abolish Pseudomonas aeruginosa resistance to antimicrobial
peptides, therefore greatly enhancing the host immune response against chronic
infections with Pseudomonas. To improve both the quality of life and the survival age of
CF patients it is crucial that new strategies are developed to manage their pulmonary
infections. Given the chronic nature of these infections preventing or abolishing
resistance is a fundamental problem. This proposal focuses on the characterization of
bacterial targets that mediate resistance to CAMPs.
患有囊性纤维化(CF)的患者发展为慢性气道感染,
机会性革兰氏阴性菌铜绿假单胞菌气道炎症
和无细菌破坏的嗜酸性浸润是这些感染的特征。它
已经显示从囊性纤维化患者分离的假单胞菌具有特异性,
脂质A结构中的毒性相关修饰。这些修改,
包括用棕榈酸酯和4-氨基阿拉伯糖取代
阳离子抗菌肽(CAMPs),先天免疫的重要组成部分,
和多粘菌素,一种CAMP抗生素。负责4-羟色胺生物合成的酶
氨基阿拉伯糖-脂质A聚集在最近重新命名为ArnBCADTEF的操纵子中。
这些基因中的任何一个的突变都消除了4-氨基阿拉伯糖添加到脂质A中,
对CAMP的抵抗。基于我们之前对ArnA的结构和生物化学工作
我们已经开发了选择性抑制ArnA的策略。在这份提案中,我们还
目标ArnD,一种假设的脱甲酰基酶,对4-
氨基阿拉伯糖-脂质A,用于生物化学和结构表征。抑制任何
这些酶将消除铜绿假单胞菌对抗菌剂的耐药性
肽,因此大大增强了宿主对慢性
感染假单胞菌。为了提高生活质量和生存年龄,
CF患者,至关重要的是,制定新的策略来管理他们的肺
感染.鉴于这些感染的慢性性质,
阻力是一个根本问题。本提案侧重于以下方面的特征:
介导对CAMPs的抗性的细菌靶标。
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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Marcelo C. Sousa其他文献
Development and Implementation of a Single-Molecule Platform to Study the Mechanism of the Beta-Barrel Assembly Machine Complex
- DOI:
10.1016/j.bpj.2019.11.475 - 发表时间:
2020-02-07 - 期刊:
- 影响因子:
- 作者:
Megan E. Mitchell;Marcelo C. Sousa - 通讯作者:
Marcelo C. Sousa
Biochemical and Structural Characterization of Enzymes Responsible of Polymyxin Resistance in Gram-Negative Bacteria
- DOI:
10.1016/j.bpj.2019.11.2887 - 发表时间:
2020-02-07 - 期刊:
- 影响因子:
- 作者:
Daniel Munoz;Marcelo C. Sousa - 通讯作者:
Marcelo C. Sousa
Structural and Biochemical Characterization of a New Zincin Protease, NleC, an Enteropathogenic Escherichia Coli Type III Secretion System Effector Responsible for Cleaving NFκB Subunit Rela
- DOI:
10.1016/j.bpj.2012.11.3035 - 发表时间:
2013-01-29 - 期刊:
- 影响因子:
- 作者:
Michelle M. Turco;Marcelo C. Sousa - 通讯作者:
Marcelo C. Sousa
Marcelo C. Sousa的其他文献
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{{ truncateString('Marcelo C. Sousa', 18)}}的其他基金
Mechanism of Transport and Folding of Outer Membrane Proteins
外膜蛋白的运输和折叠机制
- 批准号:
9900027 - 财政年份:2018
- 资助金额:
$ 37.88万 - 项目类别:
Transport and Insertion of Outer Membrane Proteins
外膜蛋白的运输和插入
- 批准号:
8289840 - 财政年份:2009
- 资助金额:
$ 37.88万 - 项目类别:
Transport and Insertion of Outer Membrane Proteins
外膜蛋白的运输和插入
- 批准号:
7565628 - 财政年份:2009
- 资助金额:
$ 37.88万 - 项目类别:
Transport and Insertion of Outer Membrane Proteins
外膜蛋白的运输和插入
- 批准号:
7842620 - 财政年份:2009
- 资助金额:
$ 37.88万 - 项目类别:
Molecular Mechanism of Retinal Guanylate Cyclase Activation by GCAPs
GCAPs 激活视网膜鸟苷酸环化酶的分子机制
- 批准号:
8065962 - 财政年份:2009
- 资助金额:
$ 37.88万 - 项目类别:
Molecular Mechanism of Retinal Guanylate Cyclase Activation by GCAPs
GCAPs 激活视网膜鸟苷酸环化酶的分子机制
- 批准号:
7653926 - 财政年份:2009
- 资助金额:
$ 37.88万 - 项目类别:
Transport and Insertion of Outer Membrane Proteins
外膜蛋白的运输和插入
- 批准号:
8417662 - 财政年份:2009
- 资助金额:
$ 37.88万 - 项目类别:
Transport and Insertion of Outer Membrane Proteins
外膜蛋白的运输和插入
- 批准号:
8603830 - 财政年份:2009
- 资助金额:
$ 37.88万 - 项目类别:
Molecular Mechanism of Retinal Guanylate Cyclase Activation by GCAPs
GCAPs 激活视网膜鸟苷酸环化酶的分子机制
- 批准号:
7805456 - 财政年份:2009
- 资助金额:
$ 37.88万 - 项目类别:
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