DAM Inhibitors: A new class of antibiotics

DAM 抑制剂：一类新型抗生素

• 批准号: 6337406
• 负责人: NORBERT O. REICH
• 金额: $ 12.12万
• 依托单位: EPIGENX PHARMACEUTICALS
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-03-15 至 2001-09-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6337406
• 关键词: DNA methylation; antibiotics; bacterial proteins; drug design /synthesis /production; drug screening /evaluation; enzyme inhibitors; methyltransferase

DESCRIPTION (provided by applicant): The objective of this six-month Phase I SBIR proposal is to develop a new class of antibiotics based on inhibiting the bacterial DNA adenine methyltransferase. DNA methylation plays a critical role in the virulence of some bacteria, including E. coli and Salmonella typhimurium. Removing the enzyme by genetic means was shown to decrease virulence over 10,000 fold in animals. These results provide clear validation of this enzyme as a drug target. Humans lack this type of DNA methylation; thus, small molecules that inhibit the bacterial enzyme are likely to be selective. EpiGenX Pharmaceuticals now has an equipped lab that is engaged in discovering cancer therapeutics aimed at the mammalian DNA methyltransferase. A similar strategy is proposed here for E.coli DAM: high throughput fluorescence-based screens using purified E.coli DAM and two historical libraries. Using this strategy we have identified several potent inhibitors of the enzyme. We propose to use computational methods to facilitate our efforts to select the most potent compounds in the two historical libraries. Realization of the objective provides EpiGenX with a clear path for antibiotic optimization through more sophisticated focused combinatorial libraries, as well as animal studies to demonstrate in vivo efficacy. PROPOSED COMMERCIAL APPLICATION: Inhibitors of the bacterial DNA adenine methyltransferase, if shown to be potent antibiotics, hold grant promise in the fight against numerous infectious diseases. The commercialization of these drugs will require several years.

描述（由申请人提供）：这六个月的第一阶段的目标 SBIR的建议是开发一类新的抗生素， 细菌DNA腺嘌呤甲基转移酶。DNA甲基化起着关键作用 在一些细菌的毒力中，包括E.杆菌和沙门氏菌 鼠伤寒。研究表明，通过遗传手段去除酶会减少 对动物的毒性超过10,000倍。这些结果提供了明确的验证 这种酶作为药物靶点。人类缺乏这种类型的DNA甲基化; 因此，抑制细菌酶的小分子很可能是 选择性的EpiGenX Pharmaceuticals现在拥有一个设备齐全的实验室， 发现针对哺乳动物DNA甲基转移酶的癌症疗法。一 本文对大肠杆菌DAM提出了类似的策略：高通量 使用纯化的大肠杆菌DAM和两个历史的 图书馆.使用这种策略，我们已经确定了几种有效的抑制剂， 酶我们建议使用计算方法来促进我们的努力 从两个历史库中选出最有效的化合物。 目标的实现为EpiGenX提供了一条明确的抗生素途径 通过更复杂的集中组合库进行优化， 以及动物研究以证明体内功效。 拟定商业应用： 细菌DNA腺嘌呤甲基转移酶的抑制剂，如果显示有效 抗生素，在与许多传染病的斗争中有着巨大的希望。 这些药物的商业化需要几年时间。