GRAM+ ANTIMICROBIALS TARGETED TO DNA POLYMERASE III

该项目的长期目标是开发新的抗生素，以治疗多重抗生素耐药（MAR）革兰氏阳性菌感染，特别是金黄色葡萄球菌和粪肠球菌。我们有针对性的复制特异性革兰氏+DNA聚合酶III（聚合酶III）和选择性聚合酶III抑制剂的6-苯胺基嘧啶类作为平台的药物设计。在第一阶段，我们都建立了pol III作为靶点的有效性，并合成了保护小鼠免受致命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）继续评价先导候选药物，3- 6-（4-羟基丁基）-2-（4-羟基丁基）-2-（三氟甲基）苯甲酰胺衍生物（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）在小鼠中的疗效和毒性;（ii）合成具有亲水性3-取代基和具有取代的6-苯胺基和6-苄基氨基的新衍生物以获得更有效的抗菌化合物;（iii）合成具有增强的溶解度和口服生物利用度的活性化合物的前药。将测试具有有效pol III和体外抗菌活性的化合物保护小鼠免受致死性葡萄球菌感染的能力。金黄色葡萄球菌感染将在小鼠中对活性化合物进行药代动力学分析，并在葡萄球菌的大腿模型中测试合适的化合物。小鼠金黄色葡萄球菌增殖。将在大腿模型中进一步测试活性化合物对E.粪菌和MAR微生物，以评价抗生素活性谱。先导候选药物的临床前研究将由Microbiotix Inc.进行。一家大型制药公司将被招募作为一个发展。健康相关性。革兰氏阳性菌MAR菌株引起的疾病管理存在危机。这项工作将导致开发新的抗生素药物作用于一个新的目标，这是技术创新和高度相关的人类健康。拟议的商业应用：制药行业正在积极寻求开发新的抗生素来攻击新的目标。我们提出的代理人不仅打击一个新的目标;他们是由一个现有的物质组成的病人。从这项工作中出现的代理人应该有很好的商业发展潜力。

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.