Overcoming Isoniazid Resistance in Tuberculosis with New Chemical Entitites

Isoniazid resistance is a major problem worldwideespecially the high level resistance caused by ST KatG mutationWe have found a stable isotope substitution improves activity against this resistant strainwhile others have used long acyl hydrazides that also improve activityWe therefore hypothesize that combining long acyl chain hydrazides to drive ST KatG binding with our MIE enhancedacylC INH warhead will generate compounds even more potent at killing drug resistant tuberculosisTo test this hypothesis we propose the following aimsSpecific AimSynthesize and characterize a library of long acyl chain hydrazides ofacylC INH designed for additional binding modes to KatG based on INH CThis library will feature linear and branched chain alkanes fromtocarbons longand their biopharmaceutical properties will be determinedSpecific AimTest the libraries binding affinities to wild type and ST KatGtheir IN NAD adduct formation yieldstheir effects on INH sensitive and resistant Mtuberculosisand their toxicity in mammalian HepGcellsThis will provide the preliminary data to support later in vivo testing in a range of INH resistant strains of Mtuberculosis Project NarrativeIsoniazid is a mainstay of tuberculosis treatmentbut isoniazid resistance is a major problemWe are developing new isoniazid derivatives combining two new approaches to target isoniazidresistanceand enable better treatment of multidrug resistant tuberculosis