Small molecule inhibitors for the study of colibactin-induced carcinogenesis by gut microbes

用于研究肠道微生物大肠杆菌素诱导癌变的小分子抑制剂

• 批准号: 10320374
• 负责人: Matthew Robert Volpe
• 金额: $ 1.62万
• 依托单位: HARVARD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-02-01 至 2022-06-10
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10320374
• 关键词: Address; Anabolism; Animal Model; Asparagine; Bacteria; Binding; Biological Assay; Biology; Biopsy; Boronic Acids; Cancer Etiology; Cell Cycle Arrest; Cells; Cellular Assay; Cessation of life; Chemicals; Chemistry; Chromosomal Instability; Clinical Research; Collaborations; Colorectal Cancer; Communities; Complex; Crystallization; DNA; DNA Adduction; DNA Alkylation; DNA Crosslinking; DNA Crosslinking Agent; DNA Double Strand Break; Development; Enzymes; Epithelial Cells; Escherichia coli; Exposure to; Fluorides; Fluorogenic Substrate; Future; Gene Cluster; Genetic; Genomic Islands; Health; Human; Human Microbiome; Hydrolysis; Hydrophobicity; In Vitro; Incidence; Infection; Institutes; Ketones; Knowledge; Length; Link; Mammalian Cell; Molecular Target; Mus; Mutagens; Mutation; Natural Products; Organism; Pathogenicity; Pathway interactions; Patients; Peptide Hydrolases; Peptides; Positioning Attribute; Prevention; Process; Production; Proteome; Reporting; Research; Risk; Risk Factors; Role; Serine; Structure; Testing; Therapeutic; Therapeutic Intervention; Time; Tissues; Toxin; Tumor Burden; Tumor Tissue; United States; Universities; Work; X-Ray Crystallography; age group; analog; base; carcinogenesis; carcinogenicity; cohort; colorectal cancer prevention; colorectal cancer progression; colorectal cancer risk; commensal microbes; covalent bond; crosslink; design; effectiveness testing; gastrointestinal epithelium; genotoxicity; gut microbes; gut microbiome; gut microbiota; high throughput screening; in vivo; inhibitor; member; microbiome research; microorganism; molecular targeted therapies; mortality; mouse model; novel; novel strategies; novel therapeutics; pathogen; periplasm; prevent; rational design; scaffold; senescence; small molecule; small molecule inhibitor; tissue culture; tool; tumor

PROJECT SUMMARY/ABSTRACT Colorectal cancer (CRC) is currently the second leading cause of cancer deaths in the United States and, as of 2018, shows an increasing mortality rate in younger age groups. The reason for this rise in mortality has not been fully explained and highlights the urgent need to better understand the causes and risk factors for CRC and develop novel strategies for its prevention and treatment. A growing body of evidence has implicated members of the human gut microbiome as potential drivers of CRC development. In particular, bacteria that produce a small molecule genotoxin known as colibactin may be key players in this process. Colibactin is produced by both commensal and pathogenic organisms which harbor the pks genomic island. Numerous studies have shown that transient infection of mammalian cells with pks+ E. coli leads to DNA crosslinking, DNA double-strand breaks, chromosomal instability, and senescence. Clinical studies have shown that pks+ bacteria are more prevalent in patients with CRC (~68%) and IBD (~40%) in comparison to healthy controls (21%) and are more abundant in tumor tissue biopsies than those from adjacent healthy tissue. In animal models, colonization with pks+ E. coli in a mouse model of CRC leads to increased tumor load relative to mice colonized with non-colibactin-producers. In perhaps the most direct evidence of colibactin’s carcinogenic potential, recent work has also shown that when mice are colonized with pks+ E. coli, colibactin directly alkylates DNA in gut epithelial cells, resulting in the formation of DNA adducts. Together, this evidence suggests that exposure to colibactin may increase risk for, or accelerate the development of, CRC via the mutagenic effects of DNA alkylation and crosslinking by colibactin. Despite this, no viable therapeutic strategy has emerged to prevent colibactin exposure, and no tools exist to study the effects of this pathway in the context of a complex, healthy gut-microbial community. This proposal aims to address these knowledge gaps by developing potent and specific small molecule inhibitors of colibactin biosynthesis. Such tool compounds will enable a more detailed study of how colibactin contributes to CRC progression and allow us to test the hypothesis that blocking colibactin production by pks+ bacteria using small molecules can lower the risk of developing CRC for the host. This research will both to explore a novel molecular target for therapeutic intervention in CRC development, as well as provide the wider scientific community with tools that will enable a more precise study of the impacts of small molecule toxins from commensal microbes on human health.

项目摘要/摘要 结直肠癌（CRC）目前是美国癌症死亡的第二大原因 并且截至2018年，年龄段的年龄段的死亡率提高。死亡率上升的原因 尚未完全解释，并强调迫切需要更好地了解原因和风险因素 CRC并制定新的预防和治疗策略。越来越多的证据已经实施 人类肠道微生物组的成员是CRC开发的潜在驱动因素。特别是细菌 在此过程中，产生一种称为肠胃痛的小分子基因毒素可能是关键参与者。结肠癌是 由含有PKS基因组岛的共生和致病生物产生的。很多的 研究表明，用PK+大肠杆菌对哺乳动物细胞的瞬时感染导致DNA交联， DNA双链断裂，染色体不稳定性和感应。临床研究表明PKS+ 与健康对照相比 （21％），在肿瘤组织活检中比来自相邻健康组织的活检更丰富。在动物中 模型，在CRC小鼠模型中用PKS+ E.大肠杆菌定殖导致相对于小鼠的肿瘤负荷增加 用非哥伦比林生殖器殖民。可能是科里氏素致癌的最直接证据 潜在的，最近的工作还表明，当小鼠用PKS+大肠杆菌定殖时，直接 肠道上皮细胞中的烷基DNA，导致DNA加合物的形成。在一起，这个证据 表明暴露于共乳蛋白可能会增加或加速CRC的风险 Colibactin的DNA烷基化和交联的诱变作用。尽管如此，没有可行的治疗策略 已经出现以防止结肠癌的暴露，并且没有任何工具来研究该途径在 复杂，健康的肠道菌群社区的背景。该建议旨在解决这些知识差距 通过开发出色的和特定的小分子抑制剂的生物合成。这样的工具化合物 将对科里巴素如何贡献CRC的进展，使我们能够测试，并能够进行更详细的研究 假设使用小分子通过PKS+细菌阻断结肠癌的产生可以降低 为主机开发CRC。这项研究都将探索一个新的分子治疗靶标 干预CRC的开发，并为更广泛的科学界提供工具，这些工具将使 更精确地研究了共生微生物对人类健康的小分子毒素的影响。