Hybrid Molecules Designed to Enhance Antibiotic Activity

描述（由申请人提供）：全球范围内耐药革兰氏阳性细菌的复苏，特别是金黄色葡萄球菌、粪肠球菌、粪肠球菌和肺炎链球菌，刺激了可以选择性攻击新细菌靶点的新型药物的发现。通过合成和研究含有两种有效药物靶点抑制剂的化合物，我们已经创建了一个新的强效抗菌药物家族，可以快速杀死所有类别的革兰氏阳性细菌。II期的结果提供了这类新型“杂交”抗生素化合物的开发候选物，这些化合物对耐药革兰氏阳性细菌具有活性。这类药物包括一种DNA聚合酶IIIC抑制剂（苯胺尿嘧啶，AU）共价连接一种拓扑异构酶/旋转酶抑制剂（氟喹诺酮，FQ）。这些新的“AU-FQ”杂化化合物比传统的pol IIIC抑制剂效力高10倍，并且在体外和体内对革兰氏阳性细菌的临床分离株具有比氟喹诺酮类药物更广泛的活性。开发候选化合物为外消旋3-{4-[1-（1-环丙基-3-羧基-4-氧-6,8-二氟-7-喹啉基）-4-（2-甲基哌嗪基）]丁基}-6-（3-乙基-4-甲基苯胺基）尿嘧啶及其S和R对映体。合理选择一种化合物作为开发候选物（CD）及其用于治疗耐药葡萄球菌和肠球菌感染的临床前开发是该II期SBIR资助竞争继续申请的主题。这个项目的目标大致是：1。优化开发候选药物的合成工艺，为临床前研究准备材料，为外包cGMP生产提供方法，并开发分析方法，以支持药品纯度测定和药代动力学分析；2. 根据大鼠体内静脉药代动力学、持续静脉滴注大鼠毒性评价和持续静脉滴注心内膜炎模型大鼠疗效评价来命名CD；3. 开展ind的临床前研究，包括GLP标准下的标准FDA要求的毒理学、病理学和毒代动力学分析；4. 向美国食品和药物管理局（FDA）提交新药研究（IND）申请以进入人体临床试验。该乳酸菌将针对具有耐药革兰氏阳性感染的住院患者进行肠外给药。GLSynthesis和Microbiotix将在成功完成该项目后继续在药物发现和开发方面的合作伙伴关系。

DESCRIPTION (provided by applicant): The worldwide resurgence of antibiotic resistant Gram-positive bacteria, especially Staphylococcus aureus, Enterococcus faecalis, Enterococcus faecium and Streptococcus pneumoniae, has stimulated discovery of novel agents that can selectively attack new bacterial targets. Through synthesis and study of compounds containing inhibitors of two validated drug targets, we have created a novel family of potent antibacterials that are rapidly bactericidal to all classes of Gram-positive bacteria. The results of phase II have provided development candidates of this new class of "hybrid" antibiotic compounds active against drug-resistant Gram-positive bacteria. The class consists of a DNA polymerase IIIC inhibitor (anilinouracil, AU) covalently attached to a topoisomerase/gyrase inhibitor (fluoroquinolone, FQ). These new "AU-FQ" hybrid compounds are tenfold more potent than conventional pol IIIC inhibitors, and have broader activity against clinical isolates of Gram-positive bacteria than the fluoroquinolones, both in vitro and in vivo. The development candidates are racemic 3-{4-[1-(1-cyclopropyl-3-carboxy-4-oxo-6,8-difluoro-7-quinolyl)-4-(2-methylpiperazinyl)]butyl}-6-(3-ethyl-4-methylanilino)uracil, and its S and R enantiomers. The rational selection of one compound as the candidate for development (CD) and its preclinical development for treatment of antibiotic-resistant staphylococcal and enterococcal infections are the subjects of the competing continuation application of this phase II SBIR grant. The goals of this project are, broadly, to: 1. optimize the process for synthesis of the development candidates, both to prepare material for preclinical studies and to provide methods for outsourcing cGMP production, and develop analytical methods to support drug product purity assays and pharmacokinetic analyses; 2. designate the CD based on IV pharmacokinetics in rats, toxicity evaluation in rats after continuous IV infusion, and efficacy evaluation in rat endocarditis models after continuous IV infusion; 3. carry out IND-enabling preclinical studies, including standard FDA required toxicology, pathology and toxicokinetic assays under GLP standards, and; 4. submit a Investigational New Drug (IND) application to the Food and Drug Administration (FDA) to enter human clinical trials. The CD will be targeted for parenteral administration to hospitalized patients with antibiotic-resistant Gram-positive infections. GLSynthesis and Microbiotix will continue a collaborative partnership in drug discovery and development by successful completion of this project.