Reversing Isoniazid Resistance By Isotopic Substitution

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Project Summary 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.