Biomimetic Peptide Aerosols for Rapid Clearance of Pulmonary MDR Tuberculosis

用于快速清除耐多药肺结核的仿生肽气雾剂

基本信息

批准号：
10344596
负责人：
Scott Hammond Medina
金额：
$ 39.65万
依托单位：
PENNSYLVANIA STATE UNIVERSITY, THE
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-11-19 至 2026-10-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10344596
关键词：
Acute Address Aerosols Antibiotic Therapy Antibiotics Antimicrobial Effect Antimycobacterial Agents Antitubercular Agents Artificial Intelligence Bacteria Bacteriology Bacteriolysis Base Sequence Binding Biochemical Pathway Biocompatible Materials Biodistribution Biological Assay Biological Availability Biomimetics Body Weight Cells Chronic Clinical Data Deposition Development Diagnosis Disease Dose Drug Combinations Drug Delivery Systems Drug Interactions Drug Kinetics Drug resistance Drug resistance in tuberculosis Drug resistant Mycobacteria Tuberculosis Electron Microscopy Engineering Epidemic Extracellular Matrix Fluorescence Fluoroquinolones Formulation Goals Health Priorities Histologic Histology Histopathology Host Defense Hyaluronic Acid Infection Invaded Kinetics Knowledge Lead Life Liquid substance Lung Lung diseases MXD1 gene Measures Membrane Metabolic Metabolism Microbe Molecular Moxifloxacin Mucociliary Clearance Multidrug-Resistant Tuberculosis Mus Mutation Mycobacterium tuberculosis Mycolic Acid Particle Size Pathogenesis Patients Peptide Antibiotics Peptides Pharmaceutical Preparations Pre-Clinical Model Property Proteins Publishing Pulmonary Tuberculosis Pulse Oximetry Recurrence Regimen Resistance Respiratory Mechanics Route Safety Scanning Series Structure Structure of parenchyma of lung Study of serum System Technology Testing Therapeutic Time Toxic effect Treatment Efficacy Treatment Protocols Tuberculosis absorption antimicrobial bactericide base combinatorial conventional therapy design effective therapy efficacy testing experimental study fitness genome sequencing global health immunogenicity improved in vivo lead candidate live cell microscopy macrophage mimetics mouse model multi-drug resistant pathogen nanomolar non-compliance novel novel therapeutic intervention novel therapeutics optimal treatments particle pathogen peptide drug peptide structure prevent pulmonary function residence resistance frequency resistance mechanism resistant strain respiratory screening self assembly side effect synergism synthetic peptide transmission process uptake whole genome

项目摘要

PROJECT SUMMARY Multidrug-resistant Tuberculosis (MDR-TB), which accounts for ~20% of recurrent TB cases and is diagnosed in 400,000 patients each year, represents an urgent global health priority that threatens to undermine US TB elimination strategies. Key to MDR-TB transmission is disruption and non-compliance with standard therapeutic regimens, which are lengthy (up to 24 months) and require high daily doses of antibiotics. The goal of this project is to develop an aerosolizable, narrow-spectrum antimicrobial biomaterial that can be paired with approved TB antibiotics to rapidly clear pulmonary MDR-TB and dramatically shorten the course of treatment. Fundamental to this strategy is a new class of protein-mimetic host defense peptides we have engineered de novo to undergo instructed self-assembly within the mycolic-acid rich outer membrane of Mycobacterium tuberculosis (Mtb). We have shown that our lead candidate, MAD1, elicits TB-specific bacteriolysis within minutes of exposure, without collateral toxicity towards protective respiratory commensals and host lung tissue. Further, these novel peptides synergistically enhance the activity of clinical antibiotics to achieve nanomolar anti-TB efficacy. However, these synthetic peptides have pharmacokinetic liabilities that include rapid clearance and limited pulmonary bioavailability, and there remain gaps in our knowledge regarding their mechanism of action when combined with other drugs. The objectives of this application are to: (i) more deeply investigate the mode of action (MoA) and drug interactions (e.g. synergy) of our lead compound MAD1 in Mtb, (ii) improve its ADME (absorption, distribution, metabolism and elimination) properties and pharmacokinetic parameters through sequence optimization and formulation into novel biomaterial aerosols, and (iii) determine the safety profile and efficacy of lead formulations in disease-relevant preclinical models. We will accomplish these objectives over three aims. In aim 1, artificial intelligence-guided structure-based sequence screening and recombineering assays will optimize MAD1’s potency against Mtb and drug-resistant strains, as well as inform on MoA. Whole-genome sequencing of resistant strains generated during these studies will characterize possible resistance mechanisms and determine the resistance frequency. Aim 2 will develop inhalable formulations of MAD1 and antibiotics utilizing our proprietary aerogel delivery system designed to exploit a key metabolic vulnerability of Mtb for rapid and pathogen-specific pulmonary therapy. Combination bacteriologic studies will assess potential for synergy towards MDR-TB and persister cells in macrophages. In aim 3, we assess the pulmonary pharmacokinetic parameters of prioritized aerogel formulations with the goal of optimizing the lung bioavailability and residence/clearance kinetics of the therapeutic carrier. We will evaluate the safety of therapeutic formulations via a series of assays (histology, pulmonary function, immunogenicity) and assess in vivo efficacy in several murine models of acute and chronic TB infection.

项目概要耐多药结核病 (MDR-TB)，约占复发性结核病病例的 20%，诊断于每年 400,000 名患者，是全球紧迫的卫生优先事项，可能会破坏美国结核病消除耐多药结核病传播的关键是破坏和不遵守标准治疗方法。该项目的目标是冗长（长达 24 个月）并且需要高剂量的抗生素。旨在开发一种可雾化的窄谱抗菌生物材料，可与批准的结核病药物搭配使用抗生素可快速清除肺部耐多药结核病并显着缩短疗程。该策略是我们从头设计的一类新型蛋白质模拟宿主防御肽指导在结核分枝杆菌 (Mtb) 富含分枝酸的外膜内进行自组装。已经表明，我们的主要候选药物 MAD1 在接触后几分钟内即可引发结核病特异性溶菌，而无需此外，这些新型肽对保护性呼吸共生体和宿主肺组织具有附带毒性。协同增强临床抗生素的活性以达到纳摩尔抗结核功效。合成肽具有药代动力学特性，包括快速清除和有限的肺功能生物利用度，并且我们对它们组合时的作用机制的了解仍然存在差距本申请的目的是：(i) 更深入地研究作用方式 (MoA)。以及我们的先导化合物 MAD1 在 Mtb 中的药物相互作用（例如协同作用），(ii) 改善其 ADME（吸收、分布、代谢和消除）特性和药代动力学参数（通过序列）优化并配制为新型生物材料气雾剂，以及 (iii) 确定其安全性和有效性我们将通过三个目标来实现这些目标。在目标 1 中，人工智能引导的基于结构的序列筛选和重组工程分析将优化 MAD1 针对 Mtb 和耐药菌株的效力，并提供全基因组信息。对这些研究期间产生的耐药菌株进行测序将描述可能的耐药机制目标 2 将开发 MAD1 和抗生素的吸入制剂。利用我们专有的气凝胶输送系统，旨在利用 Mtb 的关键代谢脆弱性，快速和病原体特异性肺部治疗的组合细菌学研究将评估协同作用的潜力。在目标 3 中，我们评估了巨噬细胞中的耐多药结核病和持续细胞。优先考虑气凝胶配方的参数，以优化肺生物利用度和我们将评估治疗制剂的安全性。通过一系列测定（组织学、肺功能、免疫原性）并评估多种体内功效急性和慢性结核感染的小鼠模型。