Bacterial Cell Wall Composition and the Influence of Antibiotics
细菌细胞壁的组成和抗生素的影响
基本信息
- 批准号:10643821
- 负责人:
- 金额:$ 33.19万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2016
- 资助国家:美国
- 起止时间:2016-09-01 至 2024-05-31
- 项目状态:已结题
- 来源:
- 关键词:AccountingAcinetobacter baumanniiAddressAnabolismAnti-Bacterial AgentsAnti-Infective AgentsAntibiotic ResistanceAntibioticsAntimicrobial ResistanceAntimycobacterial AgentsBacteremiaBacteriaBacterial InfectionsBindingBinding SitesBiochemicalBiochemistryBiologyBiophysicsCategoriesCause of DeathCell WallCellsCessation of lifeChemicalsChronicChronic Obstructive Pulmonary DiseaseChronic lung diseaseClinicalCombination Drug TherapyCommunicable DiseasesComplexCoupledDevelopmentDrug DesignDrug resistanceESKAPE pathogensElectron MicroscopyEndocarditisEnterobacterEnterococcus faeciumExhibitsExtracellular MatrixFoundationsGenerationsGenus MycobacteriumGram-Positive BacteriaHIV/AIDSIndividualInfectionInvestigationKlebsiella pneumoniaeLabelLinkLipidsMapsMeasurementMeasuresMembraneMicrobial BiofilmsMolecularMycobacterium InfectionsMycobacterium aviumMycobacterium smegmatisMycobacterium tuberculosisMycolic AcidNosocomial InfectionsOrganismParentsPathogenesisPeptidoglycanPharmaceutical PreparationsPhasePneumoniaPopulationPositioning AttributePseudomonas aeruginosaResearch DesignResistanceRespiratory Tract InfectionsRoleS phaseSamplingSepsisSignal TransductionStaphylococcus aureusStressStructureTeichoic AcidsTestingTherapeuticTuberculosisUnited StatesVancomycinantibiotic resistant infectionsantibiotic toleranceantimicrobialarabinogalactanchronic infectioncystic fibrosis patientsdesigndrug developmentexperimental studyimprovedin vivoinhibitorinnovationinsightmembermethicillin resistant Staphylococcus aureusmortalitymycobacterialnon-tuberculosis mycobacterianovel strategiesnovel therapeuticsoritavancinpathogenpreclinical developmentprogramsrecurrent infectionsolid state nuclear magnetic resonancesuccesssynergismtherapeutic candidate
项目摘要
PROJECT SUMMARY
The emergence of resistance to almost every antibiotic underscores the urgent need to introduce new
therapeutics and to understand antibiotic modes of action to help guide the development of new antimicrobials
effective against drug-resistant organisms. S. aureus together with Enterobacter species, Klebsiella
pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterococcus faecium, are categorized
as the ESKAPE pathogens and are predominant causes of hospital-acquired infection worldwide. Among
these, methicillin-resistant Staphylococcus aureus is the leading cause of mortality from antibiotic-resistant
infections in the United States. Moreover, the propensity of these pathogens to form biofilms and persister cells
is linked to recurrent and chronic infections leading to pneumonia, endocarditis, bacteremia, and sepsis.
Biofilms consist of slow-growing bacterial cells surrounded by a protective extracellular matrix, while persister
cells are dormant, highly antibiotic-tolerant bacteria that can persist in the host. Worldwide, tuberculosis is the
second most common cause of death, following deaths from HIV/AIDS, and is caused by Mycobacterium
tuberculosis. In the U.S., respiratory infections from non-tuberculosis mycobacteria (NTM) are increasing,
notably prevalent among CF patients and individuals suffering from chronic lung disease. The treatment for
NTM is complex, similar to that for TB, and requires prolonged combination drug therapy as monotherapy is
highly associated with drug resistance. We have initiated an antibiotic discovery and mode-of-action activity
program directed at the development of new therapeutics for these serious infectious diseases. In this
proposed project, we leverage our recent success in designing a new vancomycin derivative, a vancomycin-D-
octaarginine (V-r8) conjugate, that eradicates Gram-positive biofilm and persister cells and reduces
pathogenesis in vivo. We propose to uncover new discoveries regarding V-r8’s unique mode of action, as
compared to major high-value therapeutics that are now the drugs of last resort, e.g. oritavancin, towards its
development and clinical potential and to inspire the generation of new antibacterial agents. The research
design integrates interdisciplinary chemical and biochemical expertise and perspectives; mechanistic
biochemistry; and integration of solid-state NMR approaches to measure compositional changes in whole cells
and to determine distances between V-r8 and possible multiple binding sites. Furthermore, we will launch a
new experimental solid-state NMR platform to enable us to evaluate drug modes of action in mycobacteria.
This platform will be broadly applicable to investigations of complex mycobacterial cell walls and will be
specifically directed here to interrogate the activity of CPZEN-45, an exciting therapeutic candidate for the
treatment of both Mycobacterium tuberculosis and NTM.
项目概要
对几乎所有抗生素的耐药性的出现凸显了引入新抗生素的迫切需要
治疗并了解抗生素的作用方式,以帮助指导新抗菌药物的开发
对耐药微生物有效。金黄色葡萄球菌与肠杆菌属、克雷伯氏菌属
肺炎杆菌、鲍曼不动杆菌、铜绿假单胞菌和屎肠球菌等分类
作为 ESKAPE 病原体,是全世界医院获得性感染的主要原因。之中
这些,耐甲氧西林金黄色葡萄球菌是抗生素耐药性死亡的主要原因
美国的感染情况。此外,这些病原体形成生物膜和持续细胞的倾向
与导致肺炎、心内膜炎、菌血症和败血症的反复和慢性感染有关。
生物膜由生长缓慢的细菌细胞组成,周围有保护性细胞外基质,而持久性
细胞是休眠的、高度耐抗生素的细菌,可以在宿主体内持续存在。在世界范围内,结核病是
仅次于艾滋病毒/艾滋病的第二大常见死因,由分枝杆菌引起
结核。在美国,非结核分枝杆菌 (NTM) 引起的呼吸道感染正在增加,
在 CF 患者和患有慢性肺病的个体中尤其普遍。治疗方法为
NTM 很复杂,与结核病类似,并且需要长期的联合药物治疗,而单一疗法则需要长期的联合治疗。
与耐药性密切相关。我们启动了抗生素发现和作用方式活动
旨在为这些严重传染病开发新疗法的计划。在这个
拟议的项目中,我们利用最近成功设计的一种新的万古霉素衍生物,万古霉素-D-
八精氨酸 (V-r8) 缀合物,可根除革兰氏阳性生物膜和持续细胞并减少
体内发病机制。我们建议揭示有关 V-r8 独特作用模式的新发现,如
与现在作为最后手段的主要高价值治疗药物相比,例如奥利万星,朝向其
开发和临床潜力,并激发新型抗菌药物的产生。研究
设计整合了跨学科的化学和生化专业知识和观点;机械论的
生物化学;和固态核磁共振方法的集成来测量整个细胞的成分变化
并确定 V-r8 和可能的多个结合位点之间的距离。此外,我们还将推出
新的实验性固态核磁共振平台使我们能够评估药物在分枝杆菌中的作用模式。
该平台将广泛适用于复杂分枝杆菌细胞壁的研究,并将
此处专门针对 CPZEN-45 的活性进行研究,CPZEN-45 是一种令人兴奋的治疗候选药物
治疗结核分枝杆菌和 NTM。
项目成果
期刊论文数量(7)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Peptidoglycan and Teichoic Acid Levels and Alterations in Staphylococcus aureus by Cell-Wall and Whole-Cell Nuclear Magnetic Resonance.
通过细胞壁和全细胞核磁共振测定金黄色葡萄球菌中肽聚糖和磷壁酸的水平和变化。
- DOI:10.1021/acs.biochem.8b00495
- 发表时间:2018-07-03
- 期刊:
- 影响因子:2.9
- 作者:Romaniuk JAH;Cegelski L
- 通讯作者:Cegelski L
Spectral comparisons of mammalian cells and intact organelles by solid-state NMR.
通过固态核磁共振对哺乳动物细胞和完整细胞器进行光谱比较。
- DOI:10.1016/j.jsb.2018.05.007
- 发表时间:2019
- 期刊:
- 影响因子:3
- 作者:Werby,SabrinaH;Cegelski,Lynette
- 通讯作者:Cegelski,Lynette
CPMAS NMR platform for direct compositional analysis of mycobacterial cell-wall complexes and whole cells.
CPMAS NMR 平台,用于直接对分枝杆菌细胞壁复合物和全细胞进行成分分析。
- DOI:10.1016/j.jmro.2023.100127
- 发表时间:2023
- 期刊:
- 影响因子:0
- 作者:Liu,Xinyu;Brčić,Jasna;Cassell,GailH;Cegelski,Lynette
- 通讯作者:Cegelski,Lynette
Glycogen phase separation drives macromolecular rearrangement and asymmetric division in E. coli.
糖原相分离驱动大肠杆菌中的大分子重排和不对称分裂。
- DOI:10.1101/2024.04.19.590186
- 发表时间:2024
- 期刊:
- 影响因子:0
- 作者:Thappeta,Yashna;Cañas-Duarte,SilviaJ;Kallem,Till;Fragasso,Alessio;Xiang,Yingjie;Gray,William;Lee,Cheyenne;Cegelski,Lynette;Jacobs-Wagner,Christine
- 通讯作者:Jacobs-Wagner,Christine
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Lynette S Cegelski其他文献
Lynette S Cegelski的其他文献
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{{ truncateString('Lynette S Cegelski', 18)}}的其他基金
Bacterial Cell Wall Composition and the Influence of Antibiotics
细菌细胞壁的组成和抗生素的影响
- 批准号:
9319788 - 财政年份:2016
- 资助金额:
$ 33.19万 - 项目类别:
Bacterial Cell Wall Composition and the Influence of Antibiotics
细菌细胞壁的组成和抗生素的影响
- 批准号:
10174939 - 财政年份:2016
- 资助金额:
$ 33.19万 - 项目类别:
Bacterial Cell Wall Composition and the Influence of Antibiotics
细菌细胞壁的组成和抗生素的影响
- 批准号:
10401466 - 财政年份:2016
- 资助金额:
$ 33.19万 - 项目类别:
Structure, Function, and Disruption of Microbial Amyloid Assembly and Biofilm For
微生物淀粉样蛋白组装和生物膜的结构、功能和破坏
- 批准号:
7981064 - 财政年份:2010
- 资助金额:
$ 33.19万 - 项目类别:
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