Hybrid Molecules Designed to Enhance Antibiotic Activity

旨在增强抗生素活性的混合分子

• 批准号: 7408526
• 负责人: George E Wright
• 金额: $ 96.7万
• 依托单位: GLSYNTHESIS, INC.
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-05-01 至 2010-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7408526
• 关键词: Anti-Bacterial Agents; Antibiotic Resistance; Antibiotics; Biological Assay; Class; Clinical; Clinical Trials; Cyclic GMP; DNA-Directed DNA Polymerase; Development; Drug Delivery Systems; Drug Kinetics; Drug resistance; Endocarditis; Enterococcus faecalis; Enterococcus faecium; Evaluation; Family; Fluoroquinolones; Goals; Gram-Positive Bacteria; Grant; Human; Hybrids; In Vitro; Infection; Intravenous infusion procedures; Investigational Drugs; Investigational New Drug Application; Methods; Modeling; N-methylacetamide-oxotremorine M; Outsourcing; Pathology; Patients; Pharmaceutical Preparations; Phase; Process; Production; Rattus; Small Business Funding Mechanisms; Small Business Innovation Research Grant; Standards of Weights and Measures; Staphylococcus aureus; Streptococcus pneumoniae; Topoisomerase; Toxic effect; Toxicokinetics; Toxicology; United States Food and Drug Administration; Uracil; analytical method; bactericide; base; design; drug discovery; efficacy evaluation; enantiomer; in vivo; inhibitor/antagonist; novel; pol genes; pre-clinical; preclinical study; therapy development

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.

描述（由申请人提供）：抗生素抗生素抗生素阳性细菌的重新出现，尤其是金黄色葡萄球菌，粪肠球菌，肠球菌粪肠球菌和肺炎链球菌肺炎，对新颖的人的发现可以选择性地攻击新细菌。通过合成和研究含有两个经过验证药物靶标的抑制剂的化合物，我们创建了一个新型的有效抗细菌系列，这些抗菌迅速对所有类别的革兰氏阳性细菌造成杀菌。 II期的结果提供了这种新型的“杂化”抗生素化合物的发展候选，可用于耐药革兰氏阳性细菌。该类由共同附着在拓扑异构酶/陀螺酶抑制剂（Fluoroquinolone，FQ）的DNA聚合酶IIIC IIIC抑制剂（Anilinouracil，au）组成。这些新的“ AU-FQ”杂交化合物比常规的POL IIIC抑制剂高十倍，并且比体内和体内的氟喹诺酮比荧光喹诺酮类具有更广泛的活性。开发候选者是外星人3- {4- [1-（1-氯丙基-3-羧基-4-oxo-6,8-二氟-7-喹啉）-4-（2-甲基哌嗪基）]丁基} -6-（3-乙基-4-甲基烷基氨基盐）ulacil and Its ulac和Its s和ranti。合理选择一种化合物作为发育候选者（CD）及其用于治疗抗生素耐药的葡萄球菌和肠球菌感染的临床前开发是该II期SBIR赠款的竞争继续应用的主题。从广义上讲，该项目的目标是：1。优化合成开发候选者的过程，既要为临床前研究准备材料，又为外包CGMP生产提供方法，并开发了支持药物产品纯度测定和药物代动力学分析的分析方法； 2。根据大鼠的IV药代动力学指定CD，连续静脉输注后大鼠的毒性评估以及在连续静脉输注后大鼠心内膜炎模型中的疗效评估； 3。进行辅助临床前研究，包括标准FDA在GLP标准下需要毒理学，病理学和毒理学测定法，并且； 4。向食品药物管理局（FDA）提交研究新药（IND）申请，以进入人类临床试验。该CD将针对肠胃外施用，以供住院的抗生素革兰氏阳性感染患者。 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建立合作伙伴关系。