Isoniazid resistance is a major problem worldwide, especially the high level resistance caused by S315T KatG mutation. We have found a stable isotope substitution improves activity against this resistant strain, while others have used long acyl hydrazides that also improve activity. We therefore hypothesize that combining long acyl chain hydrazides to drive S315T KatG binding with our MIE enhanced [acyl-13C]INH warhead will generate compounds even more potent at killing drug resistant tuberculosis. To test this hypothesis we propose the following aims: Specific Aim 1. Synthesize and characterize a library of long acyl chain hydrazides of [acyl-13C]INH designed for additional binding modes to KatG based on INH-C10. This library will feature linear and branched chain alkanes from 8 to 12 carbons long. and their biopharmaceutical properties will be determined. Specific Aim 2. Test the libraries binding affinities to wild type and S315T KatG, their IN-NAD adduct formation yields, their effects on INH sensitive and resistant M. tuberculosis, and their toxicity in mammalian HepG2 cells. This will provide the preliminary data to support later in vivo testing in a range of INH resistant strains of M. tuberculosis.
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