Siderophore Inhibitors for Tuberculosis that Block Mycobactin Biosynthesis

阻断分枝杆菌素生物合成的结核病铁载体抑制剂

基本信息

批准号：
10368998
负责人：
Courtney C Aldrich
金额：
$ 74.54万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-04-25 至 2023-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10368998
关键词：
AIDS-Related Opportunistic Infections Acinetobacter baumannii Acute Adenosine Anabolism Anti-Bacterial Agents Antitubercular Agents Atypical Mycobacteria Bacillus Biochemical Biochemistry Biological Assay Biological Availability Cells Cellular Structures Chemistry Chronic Communicable Diseases Dose Drug Interactions Drug Kinetics Drug resistance ESKAPE pathogens Ensure Enzyme Inhibition Enzymes Escherichia coli Etiology Evaluation Extreme drug resistant tuberculosis Fluorine Generations Genetic Goals Infection Iron Iron Chelating Agents Klebsiella pneumoniae Knowledge Lead Measures Microbiology Micronutrients Modification Molecular Conformation Multi-Drug Resistance Mus Mycobacterium tuberculosis Nucleosides Oral Patients Pharmaceutical Chemistry Pharmaceutical Preparations Pharmacology Phosphotransferases Property Pseudomonas aeruginosa Research Resistance Safety Siderophores Structure Toxic effect Tuberculosis Validation Work analog base combat design drug disposition drug metabolism efficacy study extensive drug resistance genetic approach genome sequencing global health improved in vivo inhibitor lead candidate mortality mouse model multidisciplinary mutant mycobactins nanomolar novel therapeutics pathogen programs resistance frequency resistance mechanism resistant strain small molecule synergism targeted agent tuberculosis drugs uptake 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 iron for survival and obtains this essential micronutrient in vivo through the synthesis, secretion, and re-uptake of siderophores or small-molecule iron chelators known as the mycobactins. In preliminary studies using a genetic approach, we have shown mycobactin biosynthesis is essential for Mtb infection in mice. We have synthesized a selective nanomolar inhibitor of mycobactin biosynthesis termed Sal-AMS that targets the enzyme MbtA, responsible for the first and committed biosynthetic step of the mycobactins. The objectives of this application are: 1) to dramatically improve upon the in vivo efficacy of our lead compound Sal-AMS through the optimization of its pharmacokinetic parameters and potency, 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 to concurrently optimize pharmacokinetic (PK) parameters and whole-cell activity using a combination of approaches including fluorination, structural simplification of the nucleoside, and introduction of conformation constraints into the inhibitor. 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 siderophore inhibitors 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 conduct chronic toxicity studies and evaluate compounds against a panel of assays (hERG, CYP inhibition, kinase panel) to ensure safety and selectivity. In vivo efficacy studies will be done using a murine model of 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。山地车需要铁为了生存并通过合成、分泌和再摄取获得体内必需的微量营养素铁载体或小分子铁螯合剂，称为分枝杆菌素。在初步研究中使用通过遗传方法，我们已经证明分枝杆菌素生物合成对于小鼠 Mtb 感染至关重要。我们有合成了一种选择性纳摩尔分枝杆菌素生物合成抑制剂，称为 Sal-AMS，其目标是 MbtA 酶，负责分枝杆菌素生物合成的第一步和关键步骤。的目标该应用的目的是：1) 显着提高我们的先导化合物 Sal-AMS 的体内功效通过优化其药代动力学参数和效力，2）更深入地阐明 Mtb 的作用和耐药机制，3) 确定安全性和潜在的药物-药物相互作用，4) 确定与其他结核病药物的相互作用（即协同作用）。我们将完成该应用程序的总体目标是通过追求三个具体目标来实现的。在目标 1 中，我们将进行迭代基于结构的药物化学程序，可同时优化药代动力学 (PK) 参数和使用氟化、结构简化等方法组合的全细胞活性核苷，以及在抑制剂中引入构象限制。在目标 2 中，我们将进行生化和细胞研究，以评估酶抑制、靶标参与、细胞积累和全细胞对 Mtb 以及耐药菌株的活性。产生耐药菌株，然后进行全基因组分析测序将用于表征潜在的耐药机制并确定耐药性频率。最后，将进行与各种一线和二线结核病药物的联合研究评估协同效应的潜力。在目标 3 中，将对铁载体抑制剂进行体内评估以确定其作用完整的药代动力学参数，目标是改善分布容积 (Vd)、内在清除率（CL）和生物利用度（F）。我们将进行慢性毒性研究并评估化合物针对一组检测（hERG、CYP 抑制、激酶组）以确保安全性和选择性。体内将使用结核感染的小鼠模型进行功效研究。

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Development of small-molecule inhibitors of fatty acyl-AMP and fatty acyl-CoA ligases in Mycobacterium tuberculosis.

结核分枝杆菌中脂肪酰基-AMP 和脂肪酰基-CoA 连接酶小分子抑制剂的开发。

DOI：
10.1016/j.ejmech.2020.112408
发表时间：
2020-06-13
期刊：
European journal of medicinal chemistry
影响因子：
6.7
作者：
M. Baran;K. Grimes;Paul A. Sibbald;P. Fu;H. Boshoff;Daniel J. Wilson;C. Aldrich
通讯作者：
C. Aldrich

Synthesis and biological evaluation of orally active prodrugs and analogs of para-aminosalicylic acid (PAS).

对氨基水杨酸（PAS）的口服活性前药和类似物的合成和生物学评价。

DOI：
发表时间：
2022-03-15
期刊：
影响因子：
6.7
作者：
Hegde, Pooja V;Howe, Michael D;Zimmerman, Matthew D;Boshoff, Helena I M;Sharma, Sachin;Remache, Brianna;Jia, Ziyi;Pan, Yan;Baughn, Anthony D;Dartois, Veronique;Aldrich, Courtney C
通讯作者：
Aldrich, Courtney C

Polyfluorinated salicylic acid analogs do not interfere with siderophore biosynthesis.

多氟化水杨酸类似物不会干扰铁载体生物合成。

DOI：
发表时间：
2023-05
期刊：
影响因子：
0
作者：
Hegde, Pooja;Orimoloye, Moyosore O;Sharma, Sachin;Engelhart, Curtis A;Schnappinger, Dirk;Aldrich, Courtney C
通讯作者：
Aldrich, Courtney C