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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.

结核病已经折磨了人类几千年。目前的治疗是基于一种信念