GRAM+ ANTIMICROBIALS TARGETED TO DNA POLYMERASE III

该项目的长期目标是开发新的抗生素来治疗多重耐药(MAR)革兰氏+菌感染，特别是金黄色葡萄球菌和粪肠球菌。我们的目标是复制特异性的Gram+DNA聚合酶III(PolIII)和选择性的6-苯胺嘧啶类PolIII抑制剂作为药物设计的平台。在第一阶段，我们确定了PolIII作为靶标的有效性，并合成了保护小鼠免受致命金黄色葡萄球菌感染的先导药物。金黄色葡萄球菌感染。第二阶段的研究计划包括：(I)继续评价候选先导药物6-(3-乙基-4-甲基苯胺基)尿嘧啶(HB-EMAU)和6-(3-碘-4-甲基苯胺基)尿嘧啶(HB-IMAU)的疗效和毒性；(Ii)合成带有亲水性3-取代基和取代6-苯胺基和6-苯氨基的新衍生物，以获得更有效的抗菌化合物；(Iii)合成将增强溶解性和口服生物利用度的活性化合物的前体药物。具有强大的PolIII和体外抗菌活性的化合物将被测试是否有能力保护小鼠免受致命的金黄色葡萄球菌的伤害。金黄色葡萄球菌感染。活性化合物将在小鼠身上进行药代动力学分析，合适的化合物将在葡萄球菌的大腿模型中进行测试。金黄色葡萄球菌在小鼠体内的增殖。活性化合物将在大腿模型中进一步测试对粪肠球菌和MAR生物的有效性，以评估抗生素活性的光谱。主要候选药物(S)的临床前研究将由MicroBiotix Inc.进行。作为发展，将招募一家大型制药公司。与健康相关。由革兰氏+菌的MAR菌株引起的疾病的管理存在危机。这项工作将导致以新的靶点作用于新的抗生素药物的开发，并且既具有技术创新，又与人类健康高度相关。拟议的商业应用：制药业正在积极寻求开发新的抗生素来攻击新的靶点。我们建议的药物不仅打击了一个新的目标；它们被现有的物质患者组成所覆盖。从这项工作中脱颖而出的代理商应该具有良好的商业发展潜力。

The long-range objective of this project is to develop new antibiotics to treat infections with multi-antibiotic-resistant (MAR) Gram+ bacteria, especially Staphylococcus aureus and Enterococcus fecalis. We have targeted the replication-specific Gram+DNA polymerase III (pol III) and selective pol III inhibitors of the 6-anilinopyrimidine class as platforms for design of the drugs. In phase I we both established the validity of pol III as a target and synthesized lead drugs that protect mice from lethal Staph. aureus infection. The research plan for Phase II combines: (i) continued evaluation of lead drug candidates, 3-(4-hydroxybutyl) derivatives of 6-(3-ethyl-4- methylanilino) uracil (HB-EMAU) and 6-(3-iodo-4-methylanilino)uracil (HB-IMAU) for efficacy and toxicity in mice; (ii) synthesis of new derivatives with hydrophilic 3-substituents and with substituted 6-anilino and 6-benzylamino groups to obtain more potent antibacterial compounds; (iii) synthesis of prodrugs of active compounds that will have enhanced solubility and oral bioavailability. Compounds with potent pol III and antibacterial activity in vitro will be tested for ability to protect mice from lethal Staph. Aureus infections. Active compounds will be subjected to pharmacokinetic analysis in mice, and suitable compounds will be tested in a thigh model of Staph. aureus proliferation in mice. Active compounds will be tested further in the thigh model for efficacy against E. fecalis and MAR organisms to evaluate the spectrum of antibiotic activity. Preclinical studies of lead drug candidate(s) will be undertaken by Microbiotix Inc. A major pharmaceutical company will be recruited as a development. Health relatedness. There is a crisis in the management of diseases caused by MAR strains of Gram+ bacteria. This work will result in the development of new antibiotic drugs acting on a novel target, and is both technologically innovative and highly relevant to human health. PROPOSED COMMERCIAL APPLICATIONS: The drug industry is aggressively seeking to develop novel antibiotics to attack novel targets. The agents which we propose not only strike a novel target; they are covered by an existing composition of matter patient. Agents emerging from this work should have excellent potential for commercial development.