Modulation of Protein production and Degradation as an integrated approach to rapid sterilization of Drug sensitive and resistant Mtb.

调节蛋白质产生和降解作为快速灭菌药物敏感和耐药结核分枝杆菌的综合方法。

• 批准号: 10595575
• 负责人: Nader Fotouhi
• 金额: $ 547.25万
• 依托单位: GLOBAL ALLIANCE FOR TB DRUG DEVELOPMENT
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10595575
• 关键词: ATP phosphohydrolase; Acceleration; Advanced Development; Antitubercular Agents; Binding; Biochemical; Cell Death; Center for Translational Science Activities; Clinical; Clinical Trials; Collaborations; Combined Modality Therapy; Complex; DNA-Directed RNA Polymerase; Data; Development; Disease; Dose; Drug Combinations; Drug Design; Drug Targeting; Drug resistance; Drug resistance in tuberculosis; Drug resistant Mycobacteria Tuberculosis; Enzyme Inhibition; Extreme drug resistant tuberculosis; Fiber; Formulation; Genetic Transcription; Genetic study; Goals; In Vitro; Institution; Investigational Drugs; Investigational New Drug Application; Lead; Learning; Modeling; Multidrug-Resistant Tuberculosis; Mus; Mycobacterium tuberculosis; National Institute of Allergy and Infectious Disease; Natural Products; Oral; Oxazolidinones; Pathway interactions; Peptide Hydrolases; Persons; Pharmaceutical Preparations; Process; Production; Protease Inhibitor; Protein Synthesis Inhibition; Proteins; RNA Polymerase Inhibitor; Regimen; Relapse; Research Project Grants; Resistance development; Rifampin; Rifamycins; Site; Sterilization; Structure; System; Technology; Time; Translations; Treatment Protocols; Tuberculosis; candidate selection; chemical synthesis; computational chemistry; design; drug candidate; drug discovery; drug resistance development; drug-sensitive; endopeptidase Clp; in vivo; inhibitor; lead optimization; mouse model; multidisciplinary; mutant; novel; pharmacokinetics and pharmacodynamics; pre-clinical; protein degradation; proteostasis; small molecule; synergism; therapy duration; tool; tuberculosis drugs; tuberculosis treatment

The main objective of the CETR is to modulate protein production and degradation as an integrated approach to rapid sterilization of drug sensitive (DS) and drug resistant tuberculosis (DR-TB) with the ultimate goal of delivering 2 investigational new drug (IND) applications and a regimen that will be effective against both DS and DR-TB and could result in relapse-free cures of TB-infected mice in 2 months or less, while also suppressing resistance development. Historically, TB treatment regimen development has been largely empiric. Our current treatment arises from serial clinical trials performed over the course of decades. Recently, we have accelerated this empiric process using a mouse model which, thus far, has excellent predictive power. However, any rationale for these regimens is ex post facto - we really do not understand why certain combinations are better than others. Here we will endeavor to devise a better regimen from first principles. We know that inhibition of RNA polymerase (RNAP) is clinically proven to shorten therapy dramatically and that rifampin synergizes with a variety of drugs. Using genetic studies, we have found that protein degradation is a particularly vulnerable process as even modest inhibition of Clp protease activity results in cell death. We reason that multiple insults in the “proteostasis” pathway that leads from transcription through translation and protein turnover will likely result in more potent TB treatment regimens. Indeed, our preliminary in vivo data suggest this is true. This multidisciplinary CETR consortium will bring together key expertise on three major drug targets that constitute the complex and coordinated network of processes that maintain proteostasis in TB. Through this highly interconnected set of projects and cores we will be able to: Identify modulators of the Clp protease complex by discovering an orally active modulator of ClpC1, and a small molecule ClpP1P2 protease inhibitor (Project 1 and Project 2 and Cores A, B and C). Using structure guided drug discovery approaches and the latest formulation technologies these modulators will be optimized and advanced to preclinical candidate selection. We expect at least one preclinical candidate to emerge from these various approaches. Identify novel RNAP inhibitors that bind and inhibit the enzyme at a non-overlapping site than rifamycins that will therefore be effective against both drug-sensitive and DR-TB (Project 3 and Cores A, B, and C). Use of structural information and computational chemistry will guide our effort to preclinical candidate selection. Using an in vitro hollow fiber system and mouse Mtb-infection models, we will characterize the PK/PD relationships that govern the anti-TB activity and suppression of drug-resistant mutants for each drug candidate (ClpC1 modulators [Project 1], ClpP1P2 modulators [Project 2], RNAP inhibitors [Project 3] and a safer oxazolidinone already identified and currently in IND enabling studies, [Project 4]) and deliver the optimal universally active regimen.

CETR的主要目标是作为一种综合方法来调节蛋白质的生产和降解 对药物敏感(DS)和耐药结核病(DR-TB)进行快速消毒，最终目标是 提供两种研究新药(IND)应用和一种对这两种DS都有效的方案 和耐药结核病，并可能在2个月或更短的时间内治愈感染结核病的小鼠，同时还 抑制抗药性的发展。从历史上看，结核病治疗方案的开发主要是 埃皮里克。我们目前的治疗方法来自几十年来进行的一系列临床试验。最近， 我们用老鼠模型加速了这一经验性的过程，到目前为止，该模型具有极好的预测能力。 然而，这些养生法的任何理由都是事后的--我们真的不明白为什么某些 组合比其他组合更好。在这里，我们将努力从基本原则出发，设计出更好的养生方法。我们 要知道，抑制RNA聚合酶(RNAP)已被临床证明可以显著缩短治疗时间， 利福平与多种药物有协同作用。利用遗传学研究，我们发现蛋白质降解是一种 特别脆弱的过程，因为即使是轻微的抑制CLP蛋白酶活性也会导致细胞死亡。我们 原因是从转录到翻译和蛋白质平衡途径中的多重侮辱 蛋白质周转可能会导致更有效的结核病治疗方案。事实上，我们初步的活体数据 暗示这是真的。这个多学科的CETR联盟将汇集以下三个主要领域的关键专业知识 药物靶点，构成维持蛋白质平衡的复杂和协调的过程网络 结核病。通过这组高度相互关联的项目和核心，我们将能够：识别 发现口服活性调节剂ClpC1和小分子ClpP1P2的CLP蛋白酶复合体 蛋白酶抑制剂(项目1和项目2以及核心A、B和C)。利用结构导向的药物发现 这些调制器的方法和最新配方技术将被优化和推进到 临床前候选人选拔。我们预计至少有一位临床前候选人将从这些不同的 接近了。鉴定在非重叠位置结合和抑制酶的新型RNAP抑制剂 因此将对药物敏感和耐药结核病有效的利福霉素(项目3和核心A、B、 和C)。结构信息和计算化学的使用将指导我们努力寻找临床前候选人 选择。使用体外中空纤维系统和小鼠结核分枝杆菌感染模型，我们将表征 每种药物的抗结核活性和耐药突变抑制的PK/PD关系 候选(ClpC1调节剂[项目1]、ClpP1P2调节剂[项目2]、RNAP抑制剂[项目3]和a 更安全的恶唑烷酮已经确定，目前正在进行IND支持研究，[项目4])，并提供最佳 普遍有效的养生法。

项目成果

In Vitro Profiling of Antitubercular Compounds by Rapid, Efficient, and Nondestructive Assays Using Autoluminescent Mycobacterium tuberculosis.

• DOI: 10.1128/aac.00282-21
• 发表时间: 2021-07-16
• 期刊: Antimicrobial agents and chemotherapy
• 影响因子: 4.9
• 作者: Shetye GS;Choi KB;Kim CY;Franzblau SG;Cho S
• 通讯作者: Cho S

Rufomycin Exhibits Dual Effects Against Mycobacterium abscessus Infection by Inducing Host Defense and Antimicrobial Activities.

• DOI: 10.3389/fmicb.2021.695024
• 发表时间: 2021
• 期刊: Frontiers in microbiology
• 影响因子: 5.2
• 作者: Park CR;Paik S;Kim YJ;Kim JK;Jeon SM;Lee SH;Whang J;Cheng J;Suh JW;Cao J;Shetye G;Chen SN;McAlpine J;Pauli GF;Franzblau S;Cho S;Jo EK
• 通讯作者: Jo EK

Structure of the N-terminal domain of ClpC1 in complex with the antituberculosis natural product ecumicin reveals unique binding interactions.

ClpC1 的 N 端结构域与抗结核天然产物 ecumicin 复合物的结构揭示了独特的结合相互作用。

• DOI: 10.1107/s2059798320004027
• 发表时间: 2020
• 期刊: Acta crystallographica. Section D, Structural biology
• 作者: Wolf,NinaM;Lee,Hyun;Zagal,Daniel;Nam,JooWon;Oh,DongChan;Lee,Hanki;Suh,JooWon;Pauli,GuidoF;Cho,Sanghyun;Abad-Zapatero,Celerino
• 通讯作者: Abad-Zapatero,Celerino

Rufomycins or Ilamycins: Naming Clarifications and Definitive Structural Assignments.

• DOI: 10.1021/acs.jnatprod.1c00198
• 发表时间: 2021-10-22
• 期刊: Journal of natural products
• 影响因子: 5.1
• 作者: Zhou B;Achanta PS;Shetye G;Chen SN;Lee H;Jin YY;Cheng J;Lee MJ;Suh JW;Cho S;Franzblau SG;Pauli GF;McAlpine JB
• 通讯作者: McAlpine JB

New Rufomycins from Streptomyces atratus MJM3502 Expand Anti-Mycobacterium tuberculosis Structure-Activity Relationships.

• DOI: 10.1021/acs.orglett.2c02493
• 发表时间: 2022-10-14
• 期刊: ORGANIC LETTERS
• 影响因子: 5.2
• 作者: Zhou, Bin;Shetye, Gauri;Wolf, Nina M.;Chen, Shao-Nong;Qader, Mallique;Ray, G. Joseph;Lankin, David C.;Cho, Sanghyun;Cheng, Jinhua;Suh, Joo-Won;Franzblau, Scott G.;McAlpine, James B.;Pauli, Guido F.
• 通讯作者: Pauli, Guido F.