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Preclinical evaluation of compounds that inhibit cholesterol uptake in M. tuberculosis.

抑制结核分枝杆菌胆固醇摄取的化合物的临床前评估。

基本信息

批准号：
10237310
负责人：
Brian C VanderVen
金额：
$ 44.02万
依托单位：
CORNELL UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-25 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10237310
关键词：
Acute Address Adenylate Cyclase Antibiotic Therapy Antibiotics Architecture Assimilations Attenuated Bacteria Bacterial Physiology Basic Science Cells Cessation of life Chemical Stimulation Chemicals Cholesterol Cholesterol Homeostasis Complex Cyclic AMP Diffusion Disease Drug Combinations Drug Targeting Genetic Transcription Goals Granuloma Human Hypoxia Immune Immune response Infection Inflammation Inflammatory Knowledge Lesion Metabolic Pathway Metabolism Modeling Molecular Mus Mycobacterium tuberculosis Oral Pathogenesis Pathogenicity Pathologic Pathology Pathway interactions Positioning Attribute Production Regulation Research Route Series TNF gene Therapeutic Time Tissues Treatment Protocols Tuberculosis Virulence biological adaptation to stress cytokine drug candidate drug development drug discovery efficacy evaluation efficacy testing in vivo inhibitor/antagonist innovation macrophage mouse model mutant mycobacterial novel novel strategies novel therapeutics preclinical evaluation recruit response treatment strategy tuberculosis drugs tuberculosis granuloma tuberculosis treatment uptake

项目摘要

Project Summary / Abstract Cholesterol metabolism in Mtb is an attractive target for basic research and new drug development efforts. The Mtb cholesterol metabolic pathway is specific to the bacteria and mutants defective in this pathway are attenuated in various infection models. This suggests that chemically inhibiting this pathway will also attenuate Mtb virulence in vivo. We recently discovered a compound series that blocks cholesterol uptake in Mtb and stimulates cAMP overproduction in the bacteria. This is important since cAMP regulates mycobacterial central metabolism, transcription, pathogenicity, dormancy, and stress responses. Thus, chemically stimulating cAMP production in Mtb will perturb multiple different aspects of bacterial physiology in addition to cholesterol utilization. Granulomas are a major pathologic barrier that limits immune cell recruitment and antibiotic diffusion. Within a granuloma Mtb is sequestered in a cholesterol rich and hypoxic microenvironment that is thought to favor bacterial persistence. During infection, MΦ’s produce TNF-α which drives TB tissue pathology and is required to form and maintain granulomas. It is thought that TNF-α depletion can disturb the granuloma architecture and promote enhanced antibiotic availability or disrupt the granuloma microenvironment making TB antibiotics more effective. It has long been known that TNF-α production by MΦ’s can be down regulated in response to high levels of cytosolic cAMP and it is also known that Mtb-derived cAMP down regulates TNF-α production in MΦ’s. Our compound series stimulates enough Mtb-derived cAMP to down regulate TNF-α production at the infected cell level. Thus, stimulating cAMP overproduction in Mtb could be a novel strategy to reduce TNF-α levels specifically in infected MΦ’s to enhance the activity of current TB drugs. Here we propose to characterize the molecular mechanisms of how these probes block cholesterol uptake and stimulate the overproduction of cAMP in Mtb (Aim 1). We also will determine how Mtb-derived cAMP modulates: (i) the host immune response, (ii) MΦ function, and (iii) evaluate the efficacy of V-59 alone and in combination with known TB antibiotics in vivo with a goal of evaluating the therapeutic potential of V-59 (Aim 2). Because we already have a compound that has excellent potency and demonstrates in vivo efficacy via the oral route, we are well positioned to make progress with a potential TB drug candidate and novel treatment strategy.

项目摘要/摘要

项目成果

期刊论文数量（4）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Pharmacological and genetic activation of cAMP synthesis disrupts cholesterol utilization in Mycobacterium tuberculosis.

DOI：
10.1371/journal.ppat.1009862
发表时间：
2022-03
期刊：
PLoS pathogens
影响因子：
6.7
作者：
Wilburn KM;Montague CR;Qin B;Woods AK;Love MS;McNamara CW;Schultz PG;Southard TL;Huang L;Petrassi HM;VanderVen BC
通讯作者：
VanderVen BC