Novel gyrase inhibitors targeting Mycobacterium tuberculosis

针对结核分枝杆菌的新型旋转酶抑制剂

基本信息

批准号：
10725711
负责人：
Fenfei Leng
金额：
$ 23.54万
依托单位：
FLORIDA INTERNATIONAL UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-05-17 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10725711
关键词：
ATP phosphohydrolase Antibiotics Antimycobacterial Agents Antitubercular Agents Antitubercular Antibiotics Bacterial DNA Binding Biochemical Biological Biological Assay COVID-19 impact COVID-19 pandemic CRISPR interference Cells Cessation of life Clinical Communicable Diseases Complex DNA Damage DNA Gyrase Detection Development Drug Kinetics Drug resistance in tuberculosis Drug resistant Mycobacteria Tuberculosis Enzymes Evaluation Fluorescence Fluoroquinolones Funding Future Grant Growth Human In Vitro Kinetics Libraries Mediating Molecular Molecular Bank Multidrug-Resistant Tuberculosis Mutation Mycobacterium tuberculosis National Institute of Allergy and Infectious Disease Newly Diagnosed Patients Pharmaceutical Chemistry Pharmaceutical Preparations Phenotype Poison Poisoning Property Public Health Reaction Regimen Reporting Resistance Series Structure-Activity Relationship Topoisomerase Triage Tuberculosis Tuberculosis diagnosis United States National Institutes of Health World Health Organization analog cell killing combat cytotoxicity design drug metabolism fluoroquinolone resistance global health high throughput screening improved in vivo inhibitor knock-down molecular modeling mutant novel pharmacologic preclinical study pyridine quinolone resistance repository resistance mutation side effect small molecule libraries success targeted sequencing therapeutically effective transcriptome sequencing tuberculosis drugs tuberculosis treatment

项目摘要

PROJECT SUMMARY This R21 project is designed to determine structure activity relationships (SARs) of a particular chemotype of 4-(1-methylimidazo[1,2-a]pyridine-1-ium (aka CPD229 and analogs), new antimycobacterial gyrase inhibitors discovered in our recent HTS campaign targeting bacterial DNA gyrase funded by an NIAID grant 1R21AI125973. We will also improve their Mycobacterium tuberculosis (Mtb) whole cell potency and pharmacological properties. Additionally, we will determine the mechanism of action (MoA) of these new gyrase inhibitors both in vitro using purified Mtb gyrase and in vivo within Mtb. DNA gyrase, an essential enzyme to Mtb, is an excellent and validated target for discovering and developing new antibiotics to treat MDR-TB. Fluoroquinolones (FQs), one of the most important and prescribed antibiotics, target bacterial DNA gyrase. FQs are widely used as anti-TB drugs, usually as the second-line antibiotics for MDR-TB patients. However, FQ-resistant Mtb strains have been discovered threatening the utility of FQ for TB treatment. Certain FQs also have serious side effects. These newly identified antimycobacterial gyrase inhibitors, structurally distinct from FQs, provide promising starting points for development and optimization of novel antibiotics that should yield effective therapeutics capable of overcoming FQ-resistance and effectively treating MDR-TB. Success in these proposed studies would provide potent non-FQ antimycobacterial gyrase inhibitors for the development of new antibiotics/therapy for the global public health problem of multi-drug resistant TB.

项目概要该 R21 项目旨在确定特定化学型的结构活性关系 (SAR) 4-(1-甲基咪唑[1,2-a]吡啶-1-ium，又名 CPD229 及类似物)，新型抗分枝杆菌旋转酶抑制剂在我们最近由 NIAID 拨款资助的针对细菌 DNA 旋转酶的 HTS 活动中发现 1R21AI125973。我们还将提高他们的结核分枝杆菌 (Mtb) 全细胞效力和药理特性。此外，我们将确定这些新药物的作用机制 (MoA) 旋转酶抑制剂既可以在体外使用纯化的 Mtb 旋转酶，也可以在体内使用 Mtb。 DNA 旋转酶，一种必需的 Mtb 酶是发现和开发新抗生素治疗的优秀且经过验证的靶点耐多药结核病。氟喹诺酮类 (FQ) 是最重要的处方抗生素之一，以细菌 DNA 为目标旋转酶。 FQs被广泛用作抗结核药物，通常作为耐多药结核病患者的二线抗生素。然而，已发现耐 FQ 的 Mtb 菌株，威胁着 FQ 在结核病治疗中的应用。肯定 FQ 也有严重的副作用。这些新发现的抗分枝杆菌旋转酶抑制剂，在结构上与 FQ 不同，为新型抗生素的开发和优化提供了有希望的起点应该产生能够克服 FQ 耐药性并有效治疗耐多药结核病的有效疗法。这些拟议研究的成功将为以下领域提供有效的非 FQ 抗分枝杆菌旋转酶抑制剂：开发新的抗生素/疗法来解决耐多药结核病的全球公共卫生问题。