Elucidating altered lipid pathways in daptomycin-resistant pathogens
阐明达托霉素耐药病原体中脂质途径的改变
基本信息
- 批准号:9890277
- 负责人:
- 金额:$ 16.13万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-06-12 至 2022-05-31
- 项目状态:已结题
- 来源:
- 关键词:AcyltransferaseAffectAnabolismAntibiotic ResistanceAntibioticsBacteriaBiophysicsCell WallCollectionCorpus striatum structureCorynebacteriumDNA Sequence AlterationDaptomycinDevelopmentDiglyceridesEnterococcus faecalisEnterococcus faeciumEnvironmentFatty AcidsFluorescence PolarizationGenesGenomicsGlycolipidsGoalsGram-Positive BacteriaInfectionInterventionIsotope LabelingLipid Synthesis PathwayLipidsLocationMass Spectrum AnalysisMeasurementMediatingMembraneMembrane FluidityMembrane LipidsMetabolic PathwayMetabolismMethicillin ResistanceModificationMolecularMutationNatureNonesterified Fatty AcidsOutcomePathogenicityPathway interactionsPhenotypePhosphatidic AcidPhosphatidylglycerolsPhospholipidsPredispositionPropertyResistanceSourceStaphylococcus aureusStreptococcusStreptococcus oralisSystemTechniquesTestingTreatment EfficacyVancomycin resistant enterococcusWorkantimicrobialbactericidebiological adaptation to stresscell envelopedifferential expressionextracellularfatty acid biosynthesisglobal healthimprovedinhibitor/antagonistknock-downlipid biosynthesislipid metabolismlipoteichoic acidmetabolomemetabolomicsmethicillin resistant Staphylococcus aureusnew therapeutic targetnovelnovel therapeuticspathogenpathogenic bacteriapi bondpreventresistant strainsmall moleculesmall molecule inhibitortranscriptome sequencingtranscriptomics
项目摘要
Project Summary
Alteration of membrane lipids, particularly the reduction of total phosphatidylglycerols (PGs), is a common
daptomycin resistance phenotype across many species of Gram-positive bacteria. These modifications to
membrane lipid content and composition can occur through direct genetic mutations in lipid biosynthetic
pathways or indirect mutations in cell envelope stress response systems that regulate expression of membrane
and cell wall biosynthesis genes. We have previously characterized the altered membrane lipids in daptomycin-
resistant strains of methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant Enterococcus
faecalis (VRE), and Corynebacterium striatum and found that: i) daptomycin resistance also significantly affected
non-PG lipids, and ii) the changes manifested only in membrane lipids with specific fatty acid compositions in
MRSA and VRE. Lipid biosynthesis is a promising target for the development of novel therapies for the treatment
of daptomycin resistance due to the lipid-dependent mechanism of daptomycin’s bactericidal action and the
differences between eukaryotic and prokaryotic lipid biosynthetic pathways. However, the membrane lipidomes
of Gram-positive bacteria are diverse in the variety and ratios of lipid classes present and the fatty acid
compositions of those lipids. This diversity presents a challenge to finding common lipid pathways that can be
exploited to disrupt daptomycin resistance, but the central pathways of lipid synthesis and metabolism are
likely to be conserved across diverse daptomycin-resistant species. The long-term goals of this project
are to identify the common and differential pathways in lipid biosynthesis and metabolism that contribute to
daptomycin resistance among different species of Gram-positive bacteria and to identify small molecule
modulators of these pathways that can reverse daptomycin resistance. In Aim 1, we will elucidate common and
differential pathways in lipid metabolism and biosynthesis that are modified in a diverse collection of bacterial
pathogens with daptomycin resistance. We will also examine the fatty acid-dependent nature of lipid changes in
daptomycin-resistant MRSA and VRE. In Aim 2, we will modulate daptomycin resistance with small molecules
targeting lipid biosynthesis and metabolism and evaluate the effects of extracellular free fatty acids on
daptomycin resistance. We expect that the pathways that are conserved among diverse bacteria species with
daptomycin resistance will be universal targets for modulation with small molecules, and these small molecules
will improve daptomycin susceptibility by affecting the lipids and fatty acids that favor daptomycin resistance.
This project will provide new fundamental understanding of the molecular alterations that contribute to
daptomycin resistance and identify novel small molecule interventions that can be adapted into effective
therapeutics for treating infections from multiple species of daptomycin-resistant pathogens.
项目摘要
膜脂的改变,特别是总磷脂酰甘油(PG)的减少,是常见的
达托霉素耐药表型在许多种革兰氏阳性菌中存在。这些修改,
膜脂质含量和组成可以通过脂质生物合成中的直接基因突变发生,
调节膜表达的细胞包膜应激反应系统中的途径或间接突变
和细胞壁生物合成基因。我们先前已经描述了达托霉素中改变的膜脂质-
耐甲氧西林金黄色葡萄球菌(MRSA)、耐万古霉素肠球菌
粪肠杆菌(VRE)和棒状杆菌纹状体,并发现:i)达托霉素耐药性也显着影响
非PG脂质,和ii)仅在具有特定脂肪酸组成的膜脂质中表现出变化
MRSA和VRE。脂质的生物合成是一个有前途的目标,为发展新的治疗方法,
由于达托霉素杀菌作用的脂质依赖性机制和
真核生物和原核生物脂质合成途径的差异。然而,膜脂质体
革兰氏阳性菌的脂质种类和比例不同,
这些脂质的组成。这种多样性对寻找共同的脂质途径提出了挑战,
开发破坏达托霉素耐药性,但脂质合成和代谢的中心途径,
可能在不同的达托霉素耐药物种中保守。本项目的长期目标
确定脂质生物合成和代谢中的共同和差异途径,
不同革兰氏阳性菌对达托霉素的耐药性及小分子鉴定
这些途径的调节剂可以逆转达托霉素耐药性。在目标1中,我们将阐明常见和
脂质代谢和生物合成中的差异途径在不同的细菌集合中被修饰,
具有达托霉素抗性的病原体。我们还将研究脂肪酸依赖性的性质,脂质变化,
耐达托霉素MRSA和VRE。在目标2中,我们将用小分子调节达托霉素耐药性
靶向脂质生物合成和代谢,并评估细胞外游离脂肪酸对
达托霉素耐药性我们预计,在不同细菌物种中保守的途径,
达托霉素抗性将是小分子调节的通用靶标,并且这些小分子
将通过影响有利于达托霉素耐药性的脂质和脂肪酸来改善达托霉素敏感性。
该项目将提供新的分子改变的基本理解,有助于
达托霉素耐药性,并确定新的小分子干预措施,可以适用于有效的
用于治疗多种达托霉素抗性病原体感染的治疗剂。
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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Kelly M. Hines其他文献
Growth of Staphylococcus aureus in the presence of oleic acid shifts the glycolipid fatty acid profile and increases resistance to antimicrobial peptides
金黄色葡萄球菌在油酸存在下的生长会改变糖脂脂肪酸谱并增加对抗菌肽的耐药性
- DOI:
10.1101/2024.05.03.592415 - 发表时间:
2024 - 期刊:
- 影响因子:0
- 作者:
Djuro Raskovic;Gloria Alvarado;Kelly M. Hines;Libin Xu;Craig Gatto;Brian J. Wilkinson;Antje Pokorny - 通讯作者:
Antje Pokorny
Prolonged continuous infraclavicular brachial plexus perineural infusion following replantation of a mid-humeral amputation
肱骨中段截肢再植术后长时间持续锁骨下臂丛神经周围输注
- DOI:
- 发表时间:
2019 - 期刊:
- 影响因子:0.8
- 作者:
S. Clifford;B. Maggard;Kelly M. Hines - 通讯作者:
Kelly M. Hines
A rapid single-phase extraction for polar staphylococcal lipids
极性葡萄球菌脂质的快速单相萃取
- DOI:
10.1007/s00216-023-04758-9 - 发表时间:
2023 - 期刊:
- 影响因子:4.3
- 作者:
Kingsley Bimpeh;Kelly M. Hines - 通讯作者:
Kelly M. Hines
HILIC-IM-MS for Simultaneous Lipid and Metabolite Profiling of Bacteria
HILIC-IM-MS 用于同时分析细菌的脂质和代谢物
- DOI:
- 发表时间:
2023 - 期刊:
- 影响因子:0
- 作者:
Jana Carpenter;Hannah M. Hynds;Kingsley Bimpeh;Kelly M. Hines - 通讯作者:
Kelly M. Hines
Microglia Morphological Response to Mesenchymal Stromal Cell Extracellular Vesicles Demonstrates EV Therapeutic Potential for Modulating Neuroinflammation
小胶质细胞对间充质基质细胞胞外囊泡的形态反应表明 EV 具有调节神经炎症的治疗潜力
- DOI:
10.1101/2024.07.01.601612 - 发表时间:
2024 - 期刊:
- 影响因子:0
- 作者:
K. R. Daga;A. M. Larey;M. G. Morfin;Kailin Chen;S. Bitarafan;Jana Carpenter;Hannah M. Hynds;Kelly M. Hines;Levi B. Wood;Ross A. Marklein - 通讯作者:
Ross A. Marklein
Kelly M. Hines的其他文献
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{{ truncateString('Kelly M. Hines', 18)}}的其他基金
Impacts of host lipid composition on antimicrobial susceptibilities of Staphylococcus aureus
宿主脂质成分对金黄色葡萄球菌抗菌敏感性的影响
- 批准号:
10564729 - 财政年份:2022
- 资助金额:
$ 16.13万 - 项目类别:
Elucidating altered lipid pathways in daptomycin-resistant pathogens
阐明达托霉素耐药病原体中脂质途径的改变
- 批准号:
10190806 - 财政年份:2020
- 资助金额:
$ 16.13万 - 项目类别:
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