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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：
10322125
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/10322125
关键词：
AIDS-Related Opportunistic Infections Acute Anabolism Antitubercular Agents Atypical Mycobacteria Bacillus Biochemical Biological Assay Biological Availability Biotin Biotin Metabolism Pathway Cells Cellular Structures Chronic Communicable Diseases Data Drug Interactions Drug Kinetics Drug Targeting Drug resistance Ensure Enzyme Inhibition Enzymes Etiology Evaluation Extreme drug resistant tuberculosis Fluorine Generations Genetic Goals Knowledge Lead Ligase Ligation Measures Metabolism Microbiology 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 absorption analog base 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

总结