Hybrid Molecules Designed to Enhance Antibiotic Activity

描述（由申请人提供）：全球范围内耐抗生素革兰氏阳性菌的复苏，特别是金黄色葡萄球菌、粪肠球菌、屎肠球菌和肺炎链球菌，刺激了可以选择性攻击新细菌靶标的新型药物的发现。通过合成和研究含有两种经验证的药物靶点的抑制剂的化合物，我们已经创建了一种新型的强效抗菌剂家族，其对所有类别的革兰氏阳性菌都具有快速杀菌作用。第二阶段的结果提供了这类新的“杂交”抗生素化合物的开发候选者，这些化合物对耐药革兰氏阳性菌具有活性。该类药物由DNA聚合酶IIIC抑制剂（苯胺尿嘧啶，Au）与拓扑异构酶/促旋酶抑制剂（氟喹诺酮，FQ）共价连接组成。这些新的“AU-FQ”杂合化合物比常规的pol IIIC抑制剂有效十倍，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更广泛的活性。开发候选物为外消旋3-{4-[1-（1-环丙基-3-羧基-4-氧代-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对映异构体。合理选择一种化合物作为开发（CD）的候选药物及其用于治疗耐药性葡萄球菌和肠球菌感染的临床前开发是该II期SBIR资助的竞争性继续申请的主题。该项目的目标是，广泛地说，1。优化开发候选物的合成工艺，为临床前研究准备材料，并提供外包cGMP生产的方法，并开发分析方法以支持药物产品纯度测定和药代动力学分析; 2.根据大鼠IV药代动力学、大鼠持续IV输注后毒性评价和大鼠心内膜炎模型持续IV输注后疗效评价，指定CD; 3.开展IND支持的临床前研究，包括FDA要求的标准毒理学、病理学和GLP标准下的毒代动力学试验，以及; 4.向美国食品药品监督管理局（FDA）提交新药临床试验（IND）申请，以进入人体临床试验。CD将针对耐药性革兰氏阳性感染住院患者进行胃肠外给药。GLSynthesis和Microbiotix将通过成功完成该项目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.