Hybrid Molecules Designed to Enhance Antibiotic Activity

描述(申请人提供)：具有抗药性的革兰氏阳性细菌，特别是金黄色葡萄球菌、粪肠球菌、粪肠球菌和肺炎链球菌在全球范围内卷土重来，刺激了对新细菌靶标的选择性攻击的新药物的发现。通过合成和研究含有两个有效药物靶点的抑制剂的化合物，我们创造了一种新的有效抗菌剂家族，对所有类别的革兰氏阳性菌都能迅速杀菌。第二阶段的结果为这一新类别的“混合”抗生素化合物的开发提供了候选药物，这些化合物对耐药的革兰氏阳性细菌具有活性。这一类由DNA聚合酶IIIC抑制剂(苯胺尿嘧啶，AU)共价连接到拓扑异构酶/旋转酶抑制剂(氟喹诺酮，FQ)组成。这些新的“AU-FQ”杂交化合物比传统的polIIIC抑制剂有效10倍，在体外和体内对临床分离的革兰氏阳性菌比氟喹诺酮类药物具有更广泛的活性。开发的候选药物是外消旋3-{4-[1-(1-cyclopropyl-3-carboxy-4-oxo-6，8-difluoro-7-quinolyl)-4-(2-methylpiperazinyl)]butyl}-6-(3-ethyl-4-methylanilino)uracil，及其S和R对映体。合理选择一种化合物作为开发候选药物(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这一第二阶段SBIR赠款的竞争性继续申请的主题。这个项目的目标大体上是：1.优化开发候选药物的合成过程，为临床前研究准备材料和提供外包生产cGMP的方法，并开发支持药物产品纯度分析和药代动力学分析的分析方法；2.根据大鼠的静脉药代动力学、连续静脉输注后的大鼠毒性评估和持续静脉输注后的大鼠心内膜炎模型评估指定CD；3.开展IND-Enabling临床前研究，包括FDA要求的GLP标准下的毒理学、病理学和毒代动力学分析；4.向食品和药物管理局(FDA)提交研究用新药(IND)申请，以进入人体临床试验。该CD将针对住院的耐药革兰氏阳性感染患者进行非肠道给药。通过这个项目的成功完成，GL合成公司和MicroBiotix公司将继续在药物发现和开发方面建立合作伙伴关系。

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.