Optimization and mechanistic studies of halogenated phenazines and quinolines as anti-tuberculosis therapeutics

卤代吩嗪和喹啉类抗结核药物的优化及机理研究

• 批准号: 10377920
• 负责人: Robert William Huigens
• 金额: $ 19.01万
• 依托单位: UNIVERSITY OF CENTRAL FLORIDA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-03-25 至 2024-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10377920
• 关键词: Address; Antibiotic Therapy; Antibiotics; Antitubercular Agents; Bacillus; Bacteria; Binding; Biological Assay; Carbonates; Cell Wall; Cells; Cessation of life; Chelating Agents; Chemicals; Clinical; Data; Development; Disease; Dose; Down-Regulation; Drug Tolerance; Drug resistance in tuberculosis; Drug resistant Mycobacteria Tuberculosis; Edetic Acid; Extreme drug resistant tuberculosis; Foundations; Future; Genes; Granuloma; Hela Cells; HepG2; Homeostasis; Hypoxia; In Vitro; Iron; Iron Chelation; Kinetics; Knowledge; Lead; Lesion; Libraries; Lung infections; Mammalian Cell; Metabolic; Metabolism; Microbial Biofilms; Minimum Inhibitory Concentration measurement; Modification; Morbidity - disease rate; Multidrug-Resistant Tuberculosis; Mycobacterium abscessus; Mycobacterium tuberculosis; Natural Products; Nucleic Acids; Patient Noncompliance; Performance; Permeability; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacology; Phenazines; Phenotype; Prodrugs; Property; Proteins; Pseudomonas aeruginosa; Quantitative Reverse Transcriptase PCR; Regimen; Reporter; Resistance; Resolution; Rifampin; Series; Siderophores; Solubility; Source; Specificity; Staphylococcus aureus; Starvation; Structure-Activity Relationship; Testing; Therapeutic; Time; Treatment Protocols; Tuberculosis; Up-Regulation; Variant; Work; acute infection; analog; antimicrobial; bactericide; base; cystic fibrosis patients; cytotoxicity; design; drug efficacy; efficacy study; gene synthesis; improved; in vivo; inorganic phosphate; isoniazid; latent infection; lead optimization; macromolecule; metal chelator; methicillin resistant Staphylococcus aureus; microbial; mortality; mouse model; mutant; non-tuberculosis mycobacteria; novel; novel therapeutics; pathogen; pharmacophore; quinoline; quinoline analog; resistance frequency; response; scaffold; synergism; targeted treatment; transcriptome; transcriptome sequencing; tuberculosis drugs; tuberculosis treatment

Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), is responsible for staggering levels of global morbidity and mortality, with ~1.7 million deaths and ~10 million new cases each year. The shortcomings of currently available TB drugs hamper resolution of the ongoing TB crisis. The current “short course” regimen involves a cocktail of four front-line drugs administered for 6-9 months. The emergence of drug-resistant Mtb strains has complicated the already difficult task of treating TB. Driven by patient noncompliance and poor drug efficacy, ~500,000 cases of Multidrug-Resistant TB (MDR-TB) occur each year that are resistant to the two first-line drugs rifampicin (RIF) and isoniazid (INH). There is also evidence of Extensively (XDR-TB) and Totally Drug Resistant Mtb (TDR-TB), which reduce the number of therapeutics to few and none, respectively [3]. There is an urgent need for potent drugs with novel modes of action able to kill drug-resistant Mtb [4]. The ability of Mtb to establish persistent, latent infections in which Mtb are sequestered within granulomas is a hallmark of TB disease. Recent studies suggest that conditions within this lesion (i.e., hypoxia, low pH) induce a dormant metabolic state that renders bacilli phenotypically drug tolerant. Very few compounds have been identified that are active against slow-growing, dormant “persisters”. New drugs that will effectively eradicate such phenotypically resistant “persisters” may be the key to shortening treatment regimens. Our discovery of novel natural-product inspired compounds known as halogenated phenazines (HPs) that exert potent, highly selective antimicrobial activity against Mycobacterium tuberculosis provides the premise for this project. In Aim 1, we will employ a pipeline of antimicrobial assays to evaluate a library of HP analogs as well as structurally related halogenated quinolines (HQs) to define structure-activity relationships and identify optimal lead compounds. We will also work to fully understand the unique mechanism of action of HPs and HQs which appear to kill bacteria by sequestration of cytoplasmic iron. In Aim 2, in vitro ADME and in vivo PK studies will inform medicinal chemistry optimization needs and progress top compounds towards in vivo efficacy studies. To achieve compounds with enhanced pharmacological properties and in vivo performance, we will also test prodrug analogs of the best lead compounds. Completion of the proposed specific aims will yield critical knowledge about the structure-activity relationships (SAR), ADME and PK properties and mechanism of action of the HP/HQ compounds that will serve as a foundation for future lead optimization and in vivo efficacy studies.

结核病（TB），由结核分枝杆菌（Mtb）引起，是造成惊人的 全球发病率和死亡率水平，分别约为170万例死亡和1000万例新发病例 年目前可用的结核病药物的缺点阻碍了正在进行的结核病的解决 危机目前的“短期”方案包括四种一线药物的混合物， 6-9个月。耐药结核分枝杆菌菌株的出现使本已困难的 治疗结核病的任务。由于患者不依从和药物疗效差，约50万例 耐多药结核病（MDR-TB）每年都会发生，对两种一线药物具有耐药性 利福平（RIF）和异烟肼（INH）。也有证据表明广泛耐药结核和完全耐药结核 耐药结核病（TDR-TB），这减少了治疗的数量很少，没有， 分别为[3]。迫切需要具有新的作用模式的强效药物， 耐药结核分枝杆菌[4]。Mtb建立持续性潜伏感染的能力，其中Mtb 是结核病的标志。最近的研究表明， 该病变内的状况（即，缺氧、低pH）诱导休眠代谢状态， 杆菌表型耐药。很少有化合物已被确定是积极的 对抗生长缓慢休眠的“坚持者”新的药物将有效地根除这种 表型耐药的“坚持者”可能是缩短治疗方案的关键。 我们发现了新的天然产物灵感化合物称为卤代 吩嗪类药物（HP）对分枝杆菌具有强效、高选择性的抗菌活性 结核病为该项目提供了前提。在目标1中，我们将采用 抗微生物测定以评估HP类似物以及结构上相关的卤代 喹啉（HQ），以确定结构-活性关系，并确定最佳的先导化合物。 我们还将努力充分了解HP和HQ的独特作用机制， 似乎通过螯合细胞质铁来杀死细菌。在目标2中，体外ADME和体内 PK研究将告知药物化学优化需求和进展顶级化合物 用于体内功效研究。为了获得具有增强的药理学活性的化合物， 为了测试先导化合物的前体药物性质和体内性能，我们还将测试最佳先导化合物的前体药物类似物。 完成提出的具体目标将产生关于结构-活性的关键知识 HP/HQ化合物的SAR、ADME和PK性质以及作用机制 这将作为未来铅优化和体内功效研究的基础。