New Research Initiatives and Collaborative Interdisciplinary Research ($10,000-$2

新的研究计划和跨学科合作研究（10,000 美元至 2 美元）

• 批准号: 8629524
• 负责人: Jared Thomas Shaw
• 金额: $ 4.47万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-06-01 至 2015-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8629524
• 关键词: Antibiotic Resistance; Antibiotics; Area; Award; Bacteria; Bacteria FtsZ protein; Bacterial Infections; Binding Sites; Biochemical; Biochemistry; Biological Assay; Biological Factors; Cell division; Chemistry; Complement; Crystallization; Cytokinesis; Funding; Generations; Goals; Guanosine Triphosphate Phosphohydrolases; Infection; Interdisciplinary Study; Lead; Ligands; Literature; Malignant Neoplasms; Medicine; Microbiology; NMR Spectroscopy; Parents; Pharmaceutical Preparations; Photoaffinity Labels; Process; Prokaryotic Cells; Proteins; Research; Resistance; Specificity; Synthesis Chemistry; Tubulin; X-Ray Crystallography; analog; bacterial resistance; design; fighting; inhibitor/antagonist; insight; mutant; pharmacophore; prevent; programs; research study; small molecule

This application for supplemental funding describes experiments in parallel to a broader program aimed at advancing our understanding of prokaryotic cell division as a strategy for developing new antibiotics. In analogy to treating cancer by inhibiting the cytokinesis-modulating protein, tubulin, the homologous bacterial cell division protein, FtsZ, may provide an avenue for curing resistant infections. The proposed experiments in this Supplement will explore the chemistry, biochemistry and microbiology of zantrin Z3, a small molecule inhibitor of FtsZ. Although this compound has been known in the literature for many years, it was originally described in the context of many unselective inhibitors. We were able to demonstrate cross-strain specificity and the absence of unselective inhibition mechanisms common to many inhibitors studied to date. We will use synthetic chemistry, biochemical assays for GTPase inhibition, nuclear magnetic resonance spectroscopy (NMR), and conduct collaborative experiments in X-ray crystallography in order to fully understand how the function of FtsZ is modulated by analogs of this lead compound. Collectively these experiments will advance our understanding of the zantrin Z3 pharmacophore and enable the design of new compounds that will serve as leads in the search for new medicines to treat infection.

这项补充资金的申请描述了与一个更广泛的计划平行的实验，该计划旨在促进我们对原核细胞分裂的理解，作为开发新抗生素的策略。类似于通过抑制促分裂调节蛋白微管蛋白来治疗癌症，同源细菌细胞分裂蛋白FtsZ可以提供治愈耐药性感染的途径。本增刊中的拟议实验将探索Zantrin Z3（FtsZ的小分子抑制剂）的化学、生物化学和微生物学。虽然这种化合物在文献中已经知道很多年了，但它最初是在许多非选择性抑制剂的背景下描述的。我们能够证明跨菌株的特异性和非选择性抑制机制的情况下，常见的许多抑制剂研究的日期。我们将使用合成化学，生物化学测定GTdR抑制，核磁共振光谱（NMR），并在X射线晶体学中进行合作实验，以充分了解FtsZ的功能是如何通过这种先导化合物的类似物调节的。总的来说，这些实验将促进我们对zantrin Z3药效团的理解，并使新化合物的设计成为寻找治疗感染新药的先导。