The overall goal of this project is to develop our new stable isotope labeled, version of an existing tuberculosis (TB) drug, isoniazid (INH) for use in treated drug resistant TB. We hypothesize that our that isotope-enhanced compound can be developed into a powerful new drug against INH-resistant TB and multidrug resistant-TB, by addressing the following specific aims: Specific Aim 1. Determine what other INH resistance-associated mutations [acyl-13C]INH can overcome, and determine the mechanism for why [acyl-13C]INH overcomes the high INH resistance of mutant S315T KatG strains. Specific Aim 2. Develop an optimized synthesis of our compound and a Technology Transfer Protocol (TTP) for external good manufacturing processes, GMP-capable manufacture. Specific Aim 3. Collect non-Good Laboratory Practices (GLP) toxicology data on our compound to support subsequent GLP Investigational New Drug (IND) enabling studies. Successful completion of these tasks will pave the way for venture capital funding and transfer of our compound into clinical testing.
Public Health Relevance Statement: Project Narrative. Drug resistant tuberculosis is a fast-growing public health threat worldwide, and currently required lengthy and costly treatment with many side effects. This project addresses a number of key steps in the development of our new compound that is for the improved treatment of drug resistant tuberculosis.
Project Terms: active control; Address; Adverse effects; Affect; Blinded; Breath Tests; Capital Financing; Cell Nucleus; Chemistry; commercialization; Complement; Contracts; Coupling; Data; Deuterium; Development; drug discovery; Drug effect disorder; Drug Kinetics; Drug resistance; Drug resistance in tuberculosis; Free Radicals; Funding; Future; Goals; good laboratory practice; Human; Hydrogen; improved; in vivo; Investigational Drugs; isoniazid; Isoniazid resistance; Isotopes; Knowledge; Label; Laboratories; Legal patent; Literature; magnetic field; Magnetism; manufacturing process; manufacturing scale-up; Medicine; Metabolism; Multidrug-Resistant Tuberculosis; mutant; Mutation; Mycobacterium tuberculosis; novel; novel strategies; novel therapeutics; Pathway interactions; Pharmaceutical Preparations; Pharmacodynamics; Phase; Phase I Clinical Trials; Positioning Attribute; pre-clinical; Privatization; Process; Protocols documentation; Public Health; Reaction; research clinical testing; Resistance; resistance mechanism; resistant strain; Rifampin; Risk; Saint Jude Children's Research Hospital; Science; Scientist; Silk; Site; Small Business Innovation Research Grant; stable isotope; Stable Isotope Labeling; System; Technology Transfer; Testing; theories; Toxic effect; Toxicology; Treatment Cost; Tuberculosis; tuberculosis drugs; Work
