Solving a Multidrug Resistance Puzzle: Complete Loss of Lipooligosaccharide
Solving a Multidrug Resistance Puzzle: Complete Loss of Lipooligosaccharide
批准号:
9808273
负责人:
Joseph Michael Boll
金额:
$20.37万
依托单位国家:
美国
项目类别:
财政年份:
2019
资助国家:
美国
项目状态:
已结题
起止时间:
2019-06-01 至 2021-05-31
关键词:
Acinetobacter baumanniiAffinityAnabolismAntibiotic ResistanceAntibiotic TherapyAntibioticsAntimicrobial Cationic PeptidesBasic ScienceBindingBypassCell surfaceCellsCellular StructuresChargeClinicalColistinDataDevelopmentDrug DesignExposure toFutureGenesGenetic DeterminismGenetic ScreeningGenetic TranscriptionGlycerophospholipidsGoalsGram-Negative BacteriaInfectionIntelligenceKnowledgeLeadLeftLipid ALipid BilayersLipopolysaccharidesLipoproteinsMembraneMembrane ProteinsModelingMolecularMolecular AnalysisMulti-Drug ResistanceMultiple Bacterial Drug ResistanceMutationPathway interactionsPeptidoglycanPeptidyltransferasePermeabilityPhenotypePolymyxinsProteinsPublic HealthResearchResistanceResistance developmentRoleSignal TransductionSurfaceSystemTreatment FailureVaccinesantimicrobialcell envelopeclinically significantcolistin resistancehealth care settingsimprovedlipooligosaccharidemutantnovelnovel therapeuticsoverexpressionpathogenpathogenic bacteriaperiplasmresistance mechanism
中文摘要
项目概要/摘要
细菌病原体利用各种分子机制在不利的环境条件下生存。
革兰氏阴性菌修饰其外膜,外膜是由内小叶组成的不对称双层,
甘油磷脂和必需的外小叶脂寡糖或脂多糖。动杆菌
鲍曼不动杆菌是一种革兰氏阴性医院病原体,由于其能够
对抗生素产生抗药性。多药耐药A.鲍曼不动杆菌在过去已经广泛传播
十年和最后一线抗生素,如粘菌素,其靶向脂寡糖的脂质A结构域,
外膜,已经越来越多地被规定用于治疗感染。虽然粘菌素耐药性曾经很罕见,
A.鲍曼不动杆菌已经形成了一种独特的耐药机制。A.鲍曼不动杆菌可以完全关闭脂质A
生物合成,以发展对许多处方抗生素的多药耐药性,包括粘菌素。这一发现
这是令人惊讶的,因为脂多糖被认为是革兰氏阴性菌活力所需的,但这一点是令人惊讶的。
但机制证明并非如此。导致这种多药耐药表型的分子因素不是
目前尚未了解和探索治疗方案。
本提案的总体目标是描述和了解一种新的多药耐药
机制该提案的具体目的是(i)表征外膜蛋白,
支持LOS- A。Baumannii存活和(ii)BaeSR双组分系统的表征及其
监管产品。完成这些AIMS将推进我们的知识体系,以了解
脂质A在革兰氏阴性菌中重要性,并提供对所需分子机制的理解
一种新的多药耐药机制。此外,这项提案的结果也可能
从而导致新疗法和改进疫苗的开发。
英文摘要
Project Summary/Abstract
Bacterial pathogens exploit various molecular mechanisms to survive adverse environmental conditions.
Gram-negative bacteria modify their outer membrane, which is an asymmetric bilayer consisting of inner leaflet
glycerophospholipids and essential outer leaflet lipooligosaccharide or lipopolysaccharide. Acinetobacter
baumannii is a Gram-negative nosocomial pathogen that thrives in healthcare settings because of its ability to
develop resistance to antibiotics. Multidrug resistant A. baumannii have become widespread over the past
decade and last-line antibiotics such as colistin, which targets the lipid A domain of lipooligosaccharide in the
outer membrane, has been increasingly prescribed to treat infections. While colistin resistance was once rare,
A. baumannii has developed a unique resistance mechanism. A. baumannii can completely shut down lipid A
biosynthesis to develop multidrug resistance to many prescribed antibiotics, including colistin. This finding is
surprising because lipopolysaccharide was thought to be required for Gram-negative viability, but this
mechanism proves otherwise. Molecular factors that contribute to this multidrug resistance phenotype are not
understood and treatment options have not been explored.
The overall objective of this proposal is to characterize and understand a novel multidrug resistance
mechanism. The Specific Aims of this proposal are to (i) Characterize the outer membrane proteins that
support LOS- A. baumannii survival and (ii) characterization of the BaeSR two-component system and its
regulatory products. Completion of these AIMS will advance our body of knowledge to understand the
essentiality of lipid A in Gram-negative bacteria and provide understanding of a molecular mechanism required
for a novel multidrug resistance mechanism. Furthermore, the findings from this proposal could also potentially
lead to development of novel therapeutics and improved vaccines.
期刊论文(0)
专著(0)
科研奖励(0)
会议论文
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批准号:10586069
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项目类别:
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资助金额:$28.87万
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财政年份:2022
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负责人:Joseph Michael Boll
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依托单位:
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批准号:10437019
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项目类别:
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资助金额:$36.66万
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财政年份:2021
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负责人:Joseph Michael Boll
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依托单位:
Reinforcing the barrier: Understanding how cell envelope modifications promote intrinsic antimicrobial tolerance and resistance in Acinetobacter baumannii
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批准号:10605318
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项目类别:
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资助金额:$0.0万
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财政年份:2021
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负责人:Joseph Michael Boll
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依托单位:
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批准号:10880873
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项目类别:
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资助金额:$39.0万
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财政年份:2021
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负责人:Joseph Michael Boll
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依托单位:
Reinforcing the barrier: Understanding how cell envelope modifications promote intrinsic antimicrobial tolerance and resistance in Acinetobacter baumannii
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批准号:10276854
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项目类别:
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资助金额:$36.66万
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财政年份:2021
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负责人:Joseph Michael Boll
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依托单位:
Solving a Novel Multidrug Resistance Puzzle: Complete Loss of Lipooligosaccharide
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批准号:8833481
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项目类别:
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资助金额:$5.24万
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财政年份:2015
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负责人:Joseph Michael Boll
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依托单位:
海外基金