Structure-guided optimization of an in vivo active small molecule antitubercular targeting KasA

Project Summary The continued spread of drug resistant Mycobacterium tuberculosisMtbinfections has rendered tuberculosisTBa global health pandemic and pressed home the urgent need for new drugsCompounds which inhibit essential components of the Mtb cell wall rapidly cause cell death and are represented clinically by isoniazidIf any drug combination is likely to reduce treatment duration and prevent the emergence of new antibacterial resistanceit will be a sterilizing synergistically acting therapyIn this proposalour aim is to develop a new TB therapy that targets a validated druggable pathway and commences with a validated lead compoundThe longterm goal is a new drug effective against both drug susceptible and drug resistant MtbThe drug lead DGtargets KasAan essential enzyme involved in mycolic acid biosynthesisThe atomic scale interactions between KasA and DGand multiple analogs of differing chemotype have been established in high resolution X ray crystal structuresOur work corrects a previous GSK structure and shows that two molecules of DGare bound in KasADGshows synergy in killing studies with the established drug isoniazidDGisoniazid combinations lead to rapid sterilization of Mtb cultures and show synergy in a mouse model of acute Mtb infectionA DGisoniazid combination could shorten TB treatment by accelerating clearance of replicating bacteria in acute TB diseaseHerewe propose to advance lead optimization of DGOur experienced project team is comprised of academic and industrial researchers with an established track record of collaboration and the common goal of devising new antitubercular drug therapiesThe complimentary key skill sets in medicinal chemistrycheminformaticsstructural biologymicrobiologyand pharmacokinetics pharmacodynamics are all present and will be leveraged to deliver an optimized lead candidate inhibitor of Mtb KasA with enhanced in vivo efficacy as compared to the early lead DGThis will prepare us for a Phase II program that would complete the optimization and set the stage for pre IND toxicology studies Project Narrative Drug resistant Mycobacterium tuberculosisMtbinfections have rendered tuberculosisTBa global health pandemic and there is an urgent need for new antitubercular drugsCompounds which inhibit essential components of the Mtb cell wall rapidly cause cell death and are represented clinically by isoniazidThe drug lead DGtargets KasAan essential enzyme involved in mycolic acid biosynthesisshows synergy in killing studies with the front line drug isoniazid and in a mouse model of acute Mtb infectionWe propose to deliver an optimized lead candidate inhibitor of Mtb KasA with enhanced in vivo efficacy as compared to the early lead DGin preparation for a Phase II application that would target critical pre clinical studies