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.

项目总结/摘要 结直肠癌（CRC）目前是美国癌症死亡的第二大原因 截至2018年，年轻人的死亡率不断上升。死亡率上升的原因 这突出表明迫切需要更好地了解艾滋病毒/艾滋病的原因和风险因素， CRC和开发新的策略，其预防和治疗。越来越多的证据表明 人类肠道微生物组成员作为CRC发展的潜在驱动因素。特别是， 产生一种称为大肠杆菌素的小分子基因毒素可能是这一过程的关键参与者。Colibactin是 由携带PKS基因组岛的细菌和病原生物产生。许多 研究表明，pks+ E. coli导致DNA交联， DNA双链断裂、染色体不稳定和衰老。临床研究表明，PKS+ 与健康对照相比，细菌在CRC患者（约68%）和IBD患者（约40%）中更普遍 (21%），并且在肿瘤组织活组织检查中比来自邻近健康组织的那些更丰富。在动物 pks+ E.大肠杆菌在CRC小鼠模型中的表达导致肿瘤负荷相对于小鼠增加 被不产大肠杆菌素的细菌占据大肠杆菌素致癌的最直接证据 潜在的，最近的工作也表明，当小鼠与pks+ E。大肠杆菌，大肠杆菌素直接 使肠上皮细胞中的DNA烷基化，导致DNA加合物的形成。这些证据合在一起 提示暴露于大肠杆菌素可能会增加风险，或加速发展，CRC通过 大肠杆菌素对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 已经出现了预防大肠杆菌素暴露的方法，并且没有工具可以研究这种途径在 一个复杂的，健康的肠道微生物群落。本提案旨在填补这些知识空白 通过开发大肠杆菌素生物合成的有效和特异的小分子抑制剂。这种工具化合物 将使大肠杆菌素如何促进CRC进展的更详细的研究成为可能，并使我们能够测试大肠杆菌素的活性。 使用小分子阻断PKS+细菌产生大肠杆菌素可以降低 为主机开发CRC。本研究将为肿瘤治疗探索新的分子靶点， 干预CRC的发展，以及提供更广泛的科学界的工具，将使一个 更精确地研究肠道微生物小分子毒素对人类健康的影响。