Efflux pump inhibitors to reduce duration of antituberculosis therapy

外排泵抑制剂可缩短抗结核治疗的持续时间

基本信息

批准号：
7429930
负责人：
Tawanda Gumbo
金额：
$ 235.5万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-09-30 至 2012-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7429930
关键词：
ATP-Binding Cassette Transporters Acceleration Accounting Acids Aerobic Aerosols Affect Agar Air American Type Culture Collection Analysis of Variance Antibiotic Resistance Antibiotics Antihypertensive Agents Antipsychotic Agents Antitubercular Agents Area Bacillus Back Bacteria Bacterial DNA Belief Binding Blood capillaries Boutos Boxing CYP2D6 gene Calcium Channel Blockers Calibration Carbon Dioxide Cell Volumes Cell membrane Cells Cessation of life Characteristics Chest Chronic Ciprofloxacin Citric Acid Clinic Clinical Clinical Research Clinical Trials Collaborations Combined Modality Therapy Communicable Diseases Computers Condition Count Country Cytoplasm DNA Daily Data Development Dexamethasone Diffuse Disease Dose Dose Fractionation Drug Efflux Drug Exposure Drug Kinetics Drug resistance Drug usage Eating Environment Enzymes Equilibrium Ethambutol Ethionamide Ethnic group Event Exhibits Extinction (Psychology)Face Failure Family Fiber Fluorescence Fluoroquinolones Food Frequencies Gel Genes Growth Half-Life Hand Health Homidium Bromide Human Human Resources IACUC In Vitro Inbred BALB C Mice Incubated Indiana Individual Infection Infusion procedures Inhalation Exposure Isoniazid resistance Kinetics Laboratories Lead Legal patent Levaquin Life Liquid substance Logic Lung Measurement Measures Mediating Medical center Membrane Potentials Messenger RNA Metabolic Methods Modeling Molecular Molecular Weight Morbidity - disease rate Moxifloxacin Multi-Drug Resistance Multiple drug resistant Mycobacteria Tuberculosis Mus Mutation Mycobacterium tuberculosis Necrosis Neuro-Oncological Ventral Antigen 2 New York Nicotinamidase Nutrient Oils Operon Optics Oral Organ Organism Outcome Output Oxygen Oxygen measurement, partial pressure, arterial Pain Paraneoplastic Opsoclonus Ataxia Parents Patients Peroxidase Peroxidases Personal Satisfaction Pharmaceutical Preparations Pharmacodynamics Pharmacogenetics Pharmacogenomics Pharmacologic Substance Pharmacology Pharmacotherapy Phase Phenotype Plant alkaloid Plastics Play Pneumonia Poa plant Poison Population Prevention Probability Process Protein Overexpression Proteins Proton-Motive Force Protons Public Health Pump Purpose Pyrazinamide Radioactivity Radiolabeled Range Rate Reaction Relapse Relative (related person)Reporting Research Research Personnel Reserpine Resistance Respiratory distress Rifampin Role Route Safety Saline Sampling Schedule Scheme Science Scintillation Counting Series Silicone Oils Single Nucleotide Polymorphism Sister Solutions Specialist Spleen Sputum Staging Standards of Weights and Measures Sterility Sterilization for infection control Streptococcus pneumoniae Streptomycin Study Section Supplementation Surface Sushi Domain Syringes System Target Populations Teaching Hospitals Techniques Testing Therapeutic Time Translating Translations Treatment Protocols Tube Tuberculosis Tween 80 Upper arm Validation Valinomycin Verapamil Virulent Water Week Weight Work bactericide base capillary catalase clinical effect concept culture plates day density design drinking drug clearance drug efficacy efflux pump essays expectation extracellular falls fascinate flasks in vitro Model in vivo indexing inhibitor/antagonist innovation isoniazid killings macrophage man mesoxalonitrile microbial milliliter mortality mouse model pharmacodynamic model pre-clinical preclinical study programs prospective pyrazinoic acid radiotracer research study response simulation size small molecule success therapy duration treatment duration tuberculosis drugs tuberculosis treatment

项目摘要

Tuberculosis has devastated mankind for millennia. Current therapy is based on a belief that Mycobacterium tuberculosis in lung cavities exists as one of three populations: rapidly growing bacilli in areas of high oxygen that are most effectively killed by isoniazid, slowly growing bacilli under acidic conditions that are killed by pyrazinamide, and non-replicating bacilli under low oxygen tension that are killed most effectively by rifampin. We and others have recently demonstrated that parts of this belief may be incorrect. In the current proposal, I provide evidence of a central role for drug-efflux pumps to each of the first line anti-tuberculosis drugs. These drug-efflux pumps may lead to high level resistance. However, even low-level resistance efflux pumps may still provide a crucial survival advantage that enables bacilli to survive antibiotic exposure. I propose that the differential induction of drug-efflux pumps under different micro- environmental conditions may be responsible for selective effect of first line antituberculosis compounds under different oxygen and pH conditions. Induction of these pumps leads to increased mutation rates and emergence of resistance in vitro and in vivo. Inhibition of the efflux pumps by a common inhibitor will lead to acceleration of M. tuberculosis microbial kill, whether the bacilli are replicating or not. Three inexpensive efflux pump inhibitors, which are currently commercially available off patent, will be utilized to test these hypotheses in vitro and in vivo. After that, pre- clinical pharmacokinetic-pharmacodynamic studies will be performed. The drug concentrations of the efflux pump inhibitors best able to shorten duration of standard antituberculosis therapy will then be identified. Using population pharmacokinetics and pharmacogenomics, these results will be translated via Monte-Carlo simulations to identify (a) optimal dose of inhibitor best able to achieve this in humans and (b) the optimal duration of this therapy in humans. These results will then be prospectively validated.

结核病已经摧毁了数千年的人类。当前的疗法是基于信念肺腔中的结核分枝杆菌是三个人群之一：高氧气地区迅速生长异念珠菌，在酸性条件下缓慢生长的芽孢杆菌被吡嗪酰胺杀死，在低氧张力下的非重复杆菌，最有效地杀死利福平。我们和其他人最近证明了这种信念的一部分可能是不正确。在当前的提案中，我提供了药物效能的核心作用的证据泵送到第一线抗结核药物中的每一条。这些毒品泵可能导致高水平的电阻。但是，即使是低级阻力排出泵也可能仍然提供至关重要的生存优势，使杆菌能够在抗生素暴露中生存。我提出在不同微型 - 环境条件可能会导致第一线的选择性效果在不同的氧气和pH条件下，抗结核化合物具有化合物。诱导这些泵会导致突变率提高和体外耐药性的出现，并且体内。通过公共抑制剂对外排泵的抑制作用将导致加速结核病杀死的M.微生物杀死，无论杆菌是否复制。三廉价的排出泵抑制剂，目前可商购专利将用于体外和体内测试这些假设。此后，将进行临床药代动力学 - 药物动力学研究。药物排出泵抑制剂的浓度最能缩短标准持续时间然后将确定抗结核疗法。使用种群药代动力学和药物基因组学，这些结果将通过蒙特卡洛模拟翻译成识别（a）最佳抑制剂剂量最佳能够在人类中实现这一目标，（b）这种疗法在人类中的最佳持续时间。这些结果将是前瞻性的经过验证。