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

• 批准号: 9890916
• 负责人: Courtney C Aldrich
• 金额: $ 76.12万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 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/9890916
• 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/antagonist; 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

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.

总结