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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.

几千年来，结核病一直在肆虐人类。目前的治疗方法是基于一种信念肺空洞中的结核分枝杆菌存在于三个种群中：在高氧区快速生长的杆菌，这些细菌最有效地被异烟肼，在酸性条件下缓慢生长的杆菌，会被吡嗪酰胺杀死，和低氧压下的非复制杆菌，它们最有效地被利福平。我们和其他人最近证明，这种信念的一部分可能是不正确。在目前的提案中，我提供了药物外流的核心作用的证据泵到每一根抗结核一线药物。这些药物外排泵可能导致高水平的阻力。然而，即使是低阻力外排泵也可能提供关键的生存优势，使杆菌能够在抗生素下存活。我提出药物外排泵在不同微环境下的差异性诱导。环境条件可能对一线的选择效果负责不同氧气和pH条件下的抗结核化合物。诱导这些泵在体外会导致突变率增加和出现耐药性在活体内。用一种常见的抑制剂抑制外排泵将导致加速结核分枝杆菌可以杀死微生物，无论细菌是否在复制。三廉价的外排泵抑制剂，目前可以在商业上买到专利，将被用来在体外和体内检验这些假说。在那之后，之前- 将进行临床药代动力学-药效学研究。这种药最能缩短标准持续时间的外排泵抑制剂浓度然后将确定抗结核治疗方法。利用群体药代动力学和药物基因组学，这些结果将通过蒙特卡罗模拟转化为确定(A)最能在人体内实现这一目标的最佳剂量的抑制剂和(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。已验证。