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

• 批准号: 9759614
• 负责人: Justin A. Shapiro
• 金额: $ 6.12万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 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: https://reporter.nih.gov/project-details/9759614
• 关键词: Acinetobacter baumannii; Affinity; Antibiotic Resistance; Antibiotics; Area; Attention; Bacteria; Bacterial Infections; Binding; Biochemical; Biological; Biological Assay; Cell physiology; Centers for Disease Control and Prevention (U.S.); Chelating Agents; Communicable Diseases; Communities; Computer Simulation; Confocal Microscopy; Development; Docking; Drug resistance; Evaluation; Extracellular Matrix; Foundations; Future; Generations; Genes; Genomics; Gram-Negative Bacteria; Health; Healthcare; Hospital Equipment; Human; Infection; Iron; Knowledge; Libraries; Life; Light; Link; Mediating; Microbial Biofilms; Multi-Drug Resistance; Natural Products; Nature; Nosocomial Infections; Organic Synthesis; Pathogenicity; Pharmaceutical Preparations; Phenotype; Polymers; Positioning Attribute; Process; Property; Research; Resistance; Role; Route; Siderophores; Source; Structure; Structure-Activity Relationship; Surface; Testing; Therapeutic; Validation; Virulence; Virulence Factors; Virulent; Work; activity-based protein profiling; analog; base; clinically relevant; design; extracellular; fight against; fighting; global health; hydroxamate; inhibitor/antagonist; insight; interest; member; metal chelator; microbial; microbial community; mutant; novel; novel therapeutics; phenolate; pressure; prevent; protein profiling; resistant strain; scaffold; small molecule; small molecule inhibitor; therapeutic development; transcriptomics

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.

项目概要/摘要 多重耐药 (MDR) 革兰氏阴性细菌代表着全球健康危机。传统的 抗生素产生选择压力并滋生耐药性，使得我们现有的药物越来越少 有效的。作为细菌毒力因子的替代策略，靶向细菌毒力因子已引起人们的兴趣。 有可能规避这个问题。鲍曼不动杆菌的强毒力依赖于多重毒力 建立感染的机制，包括生物膜形成和铁载体介导的铁 获得。生物膜是由细胞外基质结合在一起的细菌群落， 粘附在表面并表现出增强的抗生素耐药性，并且铁载体很小 从宿主来源清除维持生命的铁的分子螯合剂。近日，一群 被称为卡维他霉素的天然产物经过结构表征并确定为 对鲍曼不动杆菌具有生物膜抑制活性。卡维他霉素含有双齿 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）；然而，恶唑啉的开环完全消除了抗生物膜活性。 这严重暗示这些分子的铁载体样性质与其它们的性质密切相关。 抗生素活性机制。在此，我们建议研究卡维他霉素以阐明 这两种临床相关毒力因子之间的生化联系。 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 卡维他霉素及其类似物，以及卡维他霉素及其类似物的生物学评价 鲍曼不动杆菌中铁载体-生物膜的关系。我们设计了一条合成路线 cahuitamycins 高度收敛，可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，以及由此产生的结构- 活性关系将用于设计功能化卡维他霉素探针分子。在 平行地，鲍曼不动杆菌中生物膜的形成将使用铁载体缺陷突变体进行评估 文库、共聚焦显微镜的表型分析和转录组分析 卡维他霉素处理的鲍曼不动杆菌。使用基于活性的蛋白质分析将能够 卡维他霉素靶标识别和计算对接将提供对机制的深入了解 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，因此能够产生高度影响力 以及新型抗毒疗法未来发展的基础工作。