Targeting Biotin Metabolism in Mycobacterium Tuberculosis

靶向结核分枝杆菌中的生物素代谢

基本信息

批准号：
10543561
负责人：
Courtney C Aldrich
金额：
$ 77.99万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-01-15 至 2023-12-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10543561
关键词：
AIDS-Related Opportunistic Infections Acute Anabolism Antitubercular Agents Atypical Mycobacteria Bacillus Biochemical Biological Biological Assay Biological Availability Biotin Biotin Metabolism Pathway Cells Cellular Structures Chronic Classification Communicable Diseases Data Drug Interactions Drug Kinetics Drug Targeting Drug resistance Ensure Enzyme Inhibition Enzymes Etiology Evaluation Generations Genetic Goals Humanities Knowledge Lead Ligase Ligation Measures Medicine Metabolism Minnesota Molecular Conformation Multi-Drug Resistance Multiple drug resistant Mycobacteria Tuberculosis Mus Mycobacterium tuberculosis Natural Products Oral Pathway interactions Patients Pharmaceutical Chemistry Pharmaceutical Preparations Property Proteins Regimen Research Resistance Safety Structure Tuberculosis Universities Validation Work Writing absorption analog cofactor combat design drug discovery drug disposition efficacy study extensive drug resistance genetic approach genome sequencing global health improved in vivo inhibitor medical schools mortality mouse model mutant mycobacterial nanomolar novel therapeutics overexpression pathogen pre-clinical preclinical development programs resistance frequency resistance mechanism resistant strain small molecular inhibitor synergism treatment duration tuberculosis drugs whole genome

项目摘要

SUMMARY Mycobacterium tuberculosis (Mtb), the principal etiological agent of tuberculosis (TB), infects over one-third of humanity and is now the leading cause of infectious disease mortality by a single pathogen. Mtb requires biotin for survival and synthesizes this essential cofactor de novo. In preliminary studies using a genetic approach, we have shown biotin biosynthesis and ligation are essential for Mtb infection in mice. We have synthesized a selective nanomolar inhibitor of biotin protein ligase termed Bio-AMS that targets the enzyme biotin protein ligase (BPL,) responsible for the ligation of biotin onto biotin-dependent enzymes. We have also identified the natural product acidomycin, which targets the final step of biotin biosynthesis catalyze by BioB. However, Bio- AMS and acidomycin have liabilities in their drug disposition properties leading to rapid clearance, poor volume of distribution, and limited oral bioavailability. There are also gaps in our knowledge regarding their mechanism of resistance and activity when combined with other TB drugs. The objectives of this application are: 1) to develop our lead compounds Bio-AMS and acidomycin through the optimization of their ADME (absorption, distribution, metabolism and elimination) properties and pharmacokinetic parameters into viable preclinical candidates, 2) to more deeply illuminate the mechanism of action and resistance in Mtb, 3) to determine the safety profile and potential drug-drug interactions, and 4) to identify interactive effects with other TB drugs (i.e. synergy). We will accomplish the overall objectives of this application by pursuing three specific aims. In aim 1, we will carry out an iterative structure-based medicinal chemistry program of Bio-AMS and acidomycin to concurrently optimize pharmacokinetic (PK) parameters and whole-cell activity using a combination of approaches including fluorination, structural simplification, and introduction of conformation constraints. In aim 2, we will perform biochemical and cellular studies to evaluate enzyme inhibition, target engagement, cellular accumulation, and whole-cell activity against Mtb as well as drug-resistant strains. Generation of resistant strains followed by whole-genome sequencing will be used to characterize potential resistance mechanisms and determine the resistance frequency. Finally, combination studies with various first and second-line TB drugs will be undertaken to assess potential for synergy. In aim 3, the Bio-AMS and acidomycin analogues will be assessed in vivo to determine their complete pharmacokinetic parameters with a goal to improve on the volume of distribution (Vd), intrinsic clearance (CL), and bioavailability (F). We will evaluate compounds against a panel of assays (hERG, CYP inhibition, Ames mutagenicity) to ensure safety and selectivity. In vivo efficacy studies will be done using murine models of acute and chronic TB infection

概括结核分枝杆菌 (Mtb) 是结核病 (TB) 的主要病原体，感染超过三分之一的人人类，现在是由单一病原体引起的传染病死亡的主要原因。结核分枝杆菌需要生物素为了生存并从头合成这种必需的辅助因子。在使用遗传方法的初步研究中，我们已经证明生物素生物合成和连接对于小鼠 Mtb 感染至关重要。我们合成了一个生物素蛋白连接酶的选择性纳摩尔抑制剂，称为 Bio-AMS，靶向生物素蛋白酶连接酶（BPL）负责将生物素连接到生物素依赖性酶上。我们还确定了天然产物酸霉素，其目标是 BioB 催化的生物素生物合成的最后一步。然而，生物 AMS 和酸霉素的药物处置特性存在缺陷，导致清除速度快、容量差分布和口服生物利用度有限。我们对其机制的了解也存在差距与其他结核病药物联合使用时的耐药性和活性。该应用程序的目标是：1) 通过优化 ADME（吸收、分布、代谢和消除）特性和药代动力学参数转化为可行的临床前候选人，2）更深入地阐明 Mtb 的作用和抵抗机制，3）确定安全性概况和潜在的药物间相互作用，以及 4) 确定与其他结核病药物（即，协同作用）。我们将通过追求三个具体目标来实现此应用程序的总体目标。在目标 1 中，我们将开展 Bio-AMS 和酸霉素的基于迭代结构的药物化学项目，以使用以下组合同时优化药代动力学 (PK) 参数和全细胞活性方法包括氟化、结构简化和引入构象约束。瞄准目标 2、我们将进行生化和细胞研究，以评估酶抑制、靶标参与、细胞积累和针对 Mtb 以及耐药菌株的全细胞活性。耐药菌的产生菌株随后进行全基因组测序将用于表征潜在的耐药机制并确定电阻频率。最后，与各种一线和二线结核病的联合研究将评估药物的协同作用潜力。在目标 3 中，Bio-AMS 和酸霉素类似物将进行体内评估以确定其完整的药代动力学参数，以改善分布容积 (Vd)、内在清除率 (CL) 和生物利用度 (F)。我们将评估化合物针对一系列检测（hERG、CYP 抑制、Ames 致突变性）以确保安全性和选择性。体内将使用急性和慢性结核感染的小鼠模型进行疗效研究

项目成果

期刊论文数量（1）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Structural and Functional Characterization of Mycobacterium tuberculosis Homoserine Transacetylase.

结核分枝杆菌高丝氨酸转乙酰酶的结构和功能特征。

DOI：
发表时间：
2023-03-10
期刊：
影响因子：
5.3
作者：
Sharma, Sachin;Jayasinghe, Yahani P;Mishra, Neeraj Kumar;Orimoloye, Moyosore O;Wong, Tsung;Dalluge, Joseph J;Ronning, Donald R;Aldrich, Courtney C
通讯作者：
Aldrich, Courtney C