Hybrid Molecules Designed to Enhance Antibiotic Activity

旨在增强抗生素活性的混合分子

• 批准号: 7225517
• 负责人: George E Wright
• 金额: $ 93.96万
• 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 2009-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7225517
• 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）：全球范围内抗生素耐药性革兰氏阳性菌，特别是金黄色葡萄球菌、粪肠球菌、屎肠球菌和肺炎链球菌的复兴，刺激了能够选择性攻击新细菌目标的新型药物的发现。通过合成和研究含有两种经过验证的药物靶点抑制剂的化合物，我们创建了一个新的强效抗菌药物家族，可以快速杀菌所有类别的革兰氏阳性细菌。第二阶段的结果为这种新型“混合”抗生素化合物的开发提供了候选方案，该化合物对耐药革兰氏阳性菌具有活性。该类药物由共价连接至拓扑异构酶/促旋酶抑制剂（氟喹诺酮，FQ）的 DNA 聚合酶 IIIC 抑制剂（苯胺尿嘧啶，AU）组成。这些新的“AU-FQ”杂合化合物比传统的 pol IIIC 抑制剂更有效十倍，并且在体外和体内均比氟喹诺酮类药物对革兰氏阳性菌的临床分离株具有更广泛的活性。开发候选者为外消旋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对映体。合理选择一种化合物作为候选开发（CD）及其治疗耐药葡萄球菌和肠球菌感染的临床前开发是本次 II 期 SBIR 资助的竞争性持续申请的主题。该项目的总体目标是： 1. 优化开发候选药物的合成工艺，既为临床前研究准备材料，也为外包 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.根据大鼠静脉药代动力学、大鼠连续静脉输注后的毒性评价、以及连续静脉输注后大鼠心内膜炎模型的疗效评价来指定CD； 3. 开展支持 IND 的临床前研究，包括 FDA 要求的 GLP 标准下的标准毒理学、病理学和毒代动力学测定，以及； 4.向美国食品药品监督管理局（FDA）提交研究性新药（IND）申请，进入人体临床试验。 CD 将针对患有抗生素耐药性革兰氏阳性感染的住院患者进行肠外给药。通过成功完成该项目，GLSynthesis 和 Microbiotix 将继续在药物发现和开发方面建立合作伙伴关系。