DAM Inhibitors: A new class of antibiotics

描述(由申请者提供)：这一为期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，其基础是抑制 细菌DNA腺嘌呤甲基转移酶。DNA甲基化起着至关重要的作用 包括大肠杆菌和沙门氏菌在内的一些细菌的毒力 鼠伤寒杆菌。通过遗传手段去除这种酶显示出减少。 对动物的毒力超过10,000倍。这些结果提供了明确的验证 将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 有选择性的。Epicenx制药公司现在拥有一个配备齐全的实验室，正在从事 发现针对哺乳动物DNA甲基转移酶的癌症治疗方法。一个 类似的策略也被提出用于大肠杆菌大坝：高吞吐量 利用纯化的大肠杆菌DAM和两个历史上的 图书馆。使用这一策略，我们已经确定了几种有效的抑制药物 这种酶。我们建议使用计算方法来促进我们的努力 在两个历史图书馆中挑选最有效的化合物。 这一目标的实现为EPIGENX提供了一条明确的抗生素途径 通过更复杂的聚焦组合库进行优化，如 以及动物研究，以证明体内的疗效。 建议的商业应用： 细菌DNA腺嘌呤甲基转移酶的抑制剂，如果被证明是有效的 抗生素，在与多种传染病的斗争中保持着巨大的希望。 这些药物的商业化将需要几年时间。

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.