Diverted Total Synthesis and Biological Evaluation of Natural Product Biofilm Inhibitors, The Cahuitamycins
天然产物生物膜抑制剂卡维他霉素的转移全合成和生物学评价
基本信息
- 批准号:9759614
- 负责人:
- 金额:$ 6.12万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2019
- 资助国家:美国
- 起止时间:2019-07-17 至 2021-07-16
- 项目状态:已结题
- 来源:
- 关键词:Acinetobacter baumanniiAffinityAntibiotic ResistanceAntibioticsAreaAttentionBacteriaBacterial InfectionsBindingBiochemicalBiologicalBiological AssayCell physiologyCenters for Disease Control and Prevention (U.S.)Chelating AgentsCommunicable DiseasesCommunitiesComputer SimulationConfocal MicroscopyDevelopmentDockingDrug resistanceEvaluationExtracellular MatrixFoundationsFutureGenerationsGenesGenomicsGram-Negative BacteriaHealthHealthcareHospital EquipmentHumanInfectionIronKnowledgeLibrariesLifeLightLinkMediatingMicrobial BiofilmsMulti-Drug ResistanceNatural ProductsNatureNosocomial InfectionsOrganic SynthesisPathogenicityPharmaceutical PreparationsPhenotypePolymersPositioning AttributeProcessPropertyResearchResistanceRoleRouteSiderophoresSourceStructureStructure-Activity RelationshipSurfaceTestingTherapeuticValidationVirulenceVirulence FactorsVirulentWorkactivity-based protein profilinganalogbaseclinically relevantdesignextracellularfight againstfightingglobal healthhydroxamateinhibitor/antagonistinsightinterestmembermetal chelatormicrobialmicrobial communitymutantnovelnovel therapeuticsphenolatepressurepreventprotein profilingresistant strainscaffoldsmall moleculesmall molecule inhibitortherapeutic developmenttranscriptomics
项目摘要
Project Summary/Abstract
Multidrug resistant (MDR) Gram-negative bacteria represent a global health crisis. Traditional
antibiotics create selective pressure and breed resistance, making our current drugs less and less
effective. Targeting of bacterial virulence factors has gained interest as an alternative strategy to
potentially circumvent this problem. Virulent Acinetobacter baumannii rely on multiple virulence
mechanisms to establish infection, including biofilm formation and siderophore-mediated iron
acquisition. Biofilms are communities of bacteria bound together by extracellular matrices that
adhere to surfaces and display enhanced antibiotic resistance, and siderophores are small-
molecule chelators that scavenge life sustaining iron from host sources. Recently, a group of
natural products dubbed the cahuitamycins were structurally characterized and determined to
have biofilm-inhibitory activity against A. baumannii. The cahuitamycins contain bidentate
chelating motifs found ubiquitously in siderophore structures (phenolate-oxazoline and
hydroxamate); however, ring-opening of the oxazoline completely abolishes anti-biofilm activity.
This heavily implies that the siderophore-like nature of these molecules is closely related to their
mechanism of antibiotic activity. Herein, we propose to study the cahuitamycins to shed light on
the biochemical connection between these two clinically relevant virulence factors.
To this end, we propose two interrelated aims focusing respectively on the organic synthesis of
cahuitamycins and analogs thereof, and on the biological evaluation of the cahuitamycins and the
siderophore-biofilm relationship in A. baumannii. We have devised a synthetic route to the
cahuitamycins that is highly convergent for the rapid generation of diverse analog panels.
Derivatives will be tested for their ability to inhibit biofilm-formation, and the resulting structure-
activity relationships will be used to design functionalized cahuitamycin probe molecules. In
parallel, biofilm formation in A. baumannii will be evaluated using siderophore-deficient mutant
libraries, phenotypic profiling by confocal microscopy, and transcriptomic analysis of
cahuitamycin-treated A. baumannii. Use of Activity-based Protein Profiling will enable
cahuitamycin target identification, and computational docking will provide insight into mechanism
of action. This proposal integrates two cutting edge research areas in the field of infectious
disease, biofilm formation and siderophores, and as such is positioned to produce highly impactful
and foundational work for the future development of novel anti-virulence therapeutics.
项目总结/摘要
多重耐药(MDR)革兰氏阴性菌代表了全球健康危机。传统
抗生素会产生选择压力,滋生抗药性,使我们现有的药物越来越少,
有效靶向细菌毒力因子作为一种替代策略已经引起了人们的兴趣,
有可能解决这个问题。鲍曼不动杆菌依赖多重毒力
建立感染的机制,包括生物膜形成和铁载体介导的铁
采集生物膜是由细胞外基质结合在一起的细菌群落,
附着在表面并显示出增强的抗生素抗性,而铁载体很小-
分子螯合剂,从宿主来源中吸收维持生命的铁。近日一组
被称为cahuitamycins的天然产物的结构特征和确定,
具有抗A.鲍曼不动杆菌。卡惠他霉素含有双齿
在铁载体结构中普遍存在的螯合基序(酚盐-恶唑啉和
异羟肟酸盐);然而,恶唑啉的开环完全消除了抗生物膜活性。
这在很大程度上意味着这些分子的铁载体样性质与它们的生物活性密切相关。
抗生素活性机制。在此,我们建议研究cahuitamycins,以阐明
这两种临床相关毒力因子之间的生物化学联系。
为此,我们提出了两个相互关联的目标,分别侧重于有机合成,
卡惠他霉素及其类似物的生物学评价,
铁载体-生物膜关系。鲍曼不动杆菌。我们设计了一种合成路线,
cahuitamycins是高度收敛的快速生成不同的模拟面板。
将测试衍生物抑制生物膜形成的能力,以及所得结构-
活性关系将用于设计官能化卡惠他霉素探针分子。在
平行,A.将使用铁载体缺陷突变体
文库,共聚焦显微镜表型分析,和转录组学分析,
cahuitamycin处理A.鲍曼不动杆菌。使用基于活性的蛋白质分析将使
cahuitamycin靶点鉴定和计算对接将提供深入了解机制
的行动。该提案整合了传染病领域的两个前沿研究领域,
疾病,生物膜形成和铁载体,因此被定位为产生高度影响力的
为今后开发新型抗病毒治疗药物奠定了基础。
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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Justin A. Shapiro其他文献
Total Synthesis of the Reported Structure of Cahuitamycin A
卡维他霉素 A 已报道结构的全合成
- DOI:
- 发表时间:
2020 - 期刊:
- 影响因子:0
- 作者:
Justin A. Shapiro;Savannah J. Post;W. Wuest - 通讯作者:
W. Wuest
The Chemistry and Biology of Iron-Scavenging Natural Products from Pathogenic Acinetobacter baumannii
- DOI:
10.7936/k7x066f6 - 发表时间:
2017 - 期刊:
- 影响因子:0
- 作者:
Justin A. Shapiro - 通讯作者:
Justin A. Shapiro
Innovation Centers in Health Care Delivery Systems: Structures for Success (Preprint)
医疗保健服务系统创新中心:成功的结构(预印本)
- DOI:
- 发表时间:
2021 - 期刊:
- 影响因子:0
- 作者:
O. Bhattacharyya;Justin A. Shapiro;E. Schneider - 通讯作者:
E. Schneider
Justin A. Shapiro的其他文献
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