Bacterial and Molecular Determinants of Mycobacterial Impermeability

分枝杆菌不渗透性的细菌和分子决定因素

基本信息

批准号：
10749613
负责人：
Marcos M. Pires
金额：
$ 74.19万
依托单位：
UNIVERSITY OF VIRGINIA
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-08-02 至 2028-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10749613
关键词：
Adopted Alkynes Antibiotic Therapy Antibiotics Azides Bacteria Biochemical Reaction Biological Assay Biology Cell Compartmentation Cell Wall Cell membrane Cells Chemical Structure Chemicals Chemistry Chimeric Proteins Cholesterol Complex Cytoplasm Data Destinations Detection Dose Drug resistance Environment Escherichia coli Fluorescence Foundations Gatekeeping Genes Genetic Genetic Determinism Genetic Screening Growth Home Hydrophobicity Label Libraries Link Lipids Location Mammalian Cell Maps Membrane Metabolic Methods Modeling Molecular Mycobacterium tuberculosis Organelles Organism Pathogenesis Penetration Peptidoglycan Permeability Persons Pharmaceutical Chemistry Pharmaceutical Preparations Positioning Attribute Predisposition Public Health Publishing Reporting Rifampin Series Specificity Structure Testing Translations Tuberculosis Work bacterial genetics barrier to testing biomaterial compatibility cell envelope cheminformatics combinatorial drug discovery efflux pump grasp improved member model organism molecular sieving mycobacterial non-tuberculosis mycobacteria pathogen pathogenic bacteria screening small molecule tool tuberculosis drugs tuberculosis treatment uptake

项目摘要

Project Summary The typical course of treatment for uncomplicated Mycobacterium tuberculosis infection comprises four antibiotics and lasts for at least six months. The impermeability of the multi-layered M. tuberculosis cell envelope has long been linked to the organism’s intrinsically-poor drug susceptibility. While the outer ‘myco’ membrane is hypothesized to be the primary barrier to accessing antibiotic targets in the peptidoglycan or cytoplasm, other facets of the envelope likely contribute. Moreover, compared to the model organism Escherichia coli and to mammalian cells, the field has only a rudimentary understanding of the kinds of compounds that can permeate M. tuberculosis. Based on published and preliminary data, the PIs hypothesize that M. tuberculosis impermeability is a consequence of envelope composition as well as the target location and chemical structure of the compound. A major hurdle to testing this hypothesis is the lack of high-throughput tools for identifying bacterial and molecular factors that control compound permeation across envelope layers. In this proposal, The PIs develop and deploy two complementary methods for defining the bacterial and molecular determinants of M. tuberculosis impermeability. They will first test the relative importance of various M. tuberculosis factors in molecule gate-keeping. Next, they will globally determine the M. tuberculosis genes that contribute to mycomembrane impermeability. Finally, they will comprehensively determine the structural motifs associated with M. tuberculosis mycomembrane permeation or lack thereof. Successful completion of these aims will lay the foundation for medicinal chemistry efforts to improve M. tuberculosis uptake of both existing drugs and newly-discovered compounds. The methods that the PIs use to achieve these aims are easily ported to species for which envelope permeability is also treatment-limiting, e.g., non-tuberculous mycobacteria (NTMs) and Gram-negatives.

项目概要无并发症的结核分枝杆菌感染的典型治疗过程包括四种抗生素，可持续至少六个月。结核病细胞包膜长期以来一直与生物体本质上较差的药物敏感性有关。虽然外层“真菌”膜被打乱，成为获取抗生素的主要障碍肽聚糖或细胞质中的目标，包膜的其他方面可能有所贡献。与模式生物大肠杆菌和哺乳动物细胞相比，该领域只有对可渗透结核分枝杆菌的化合物种类的初步了解。已发表的初步数据，表明结核分枝杆菌不渗透性是一项重要指标包膜成分以及目标位置和化学结构的结果检验这一假设的一个主要障碍是缺乏用于识别的高通量工具。控制化合物跨包膜层渗透的细菌和分子因素。提案中，PI 开发并部署了两种互补的方法来定义细菌和他们将首先测试结核分枝杆菌不渗透性的分子决定因素。接下来，他们将在全球范围内确定结核分枝杆菌的分子守门因素。最后，它们会导致菌膜不渗透性。全面确定与结核分枝杆菌菌膜相关的结构基序渗透或缺乏渗透的成功完成将为医学奠定基础。提高结核分枝杆菌对现有药物和新发现药物的吸收的化学努力 PI 用于实现这些目标的方法很容易移植到物种中。其包膜通透性也是治疗限制的，例如非结核分枝杆菌 (NTM) 和革兰氏阴性菌。