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: 10193679
• 负责人: Robert William Huigens
• 金额: $ 24.12万
• 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 2023-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10193679
• 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; 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; 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.

由结核分枝杆菌(Mtb)引起的结核病(TB)是造成 全球发病率和死亡率水平，分别有约170万人死亡和约1000万新病例 年。现有结核病药物的缺点阻碍了对持续结核病的解决。 危机。目前的“短疗程”疗法包括四种前线药物的鸡尾酒疗法。 6-9个月。耐药结核分枝杆菌菌株的出现使本已困难的问题复杂化。 治疗结核病的任务。在患者不依从和药物疗效不佳的推动下，约50万例 耐多药结核病(MDR-TB)每年都会发生，对这两种一线药物都有耐药性 利福平(RIF)和异烟肼(INH)。也有证据表明广泛的(广泛耐药结核病)和完全 耐药结核分枝杆菌(TDR-TB)，将治疗药物的数量减少到很少甚至没有， 分别为[3]。迫切需要能够杀死人的具有新作用模式的强效药物 耐药结核分枝杆菌[4]。结核分枝杆菌建立持续、潜伏感染的能力 肉芽肿内的隔离是结核病的一个标志。最近的研究表明 病变内的条件(即低氧、低pH)诱导休眠的代谢状态，使 耐药杆菌表型。几乎没有发现有活性的化合物。 反对生长缓慢、处于休眠状态的“顽固者”。将有效根除这种疾病的新药 表型耐药的“持久者”可能是缩短治疗方案的关键。 我们发现了一种名为卤代化合物的新型天然产物 吩嗪类(HPS)对分枝杆菌具有高效、高度选择性的抗菌活性 结核病为这一项目提供了前提。在目标1中，我们将采用一条管道 评估Hp类似物文库以及结构相关的卤代化合物的抗菌试验 喹啉类化合物(HQs)，以定义结构-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HPS和HQ的独特作用机制，即 似乎通过隔离细胞质铁来杀死细菌。在AIM 2中，体外ADME和体内 PK研究将为药物化学优化需求和顶级化合物提供信息 走向体内药效研究。获得具有增强药理作用的化合物 除了性能和体内表现，我们还将测试最好的先导化合物的前药类似物。 完成提议的具体目标将产生关于结构-活动的批判性知识 HP/HQ化合物的构效关系、ADME和PK性质及作用机理 这将为未来的先导优化和体内疗效研究奠定基础。