RATIONAL DESIGN OF ENZYME INHIBITORS AS POTENTIAL DRUGS TO TREAT TUBERCULOSIS, MALARIA, AFRICAN SLEEPING SICKNESS, AND CHAGAS DISEASE.

We will:(1) identify essential enzymes in pathogens by genetic knockout/knockdown techniques(2) Isolate genes of these enzymes, and express and purify them in bacteria(3) Develop x-ray structures of these enzyme targets.(4) Investigate the chemical mechanism of these enzymes.(5) Use mechanistic information and structure to design inhibitors or covalent inactivators of these enzyme targets.(6) Synthesize and test these inhibitors and inactivators vs. these targets, including the elaboration of x-ray structures of these compounds bound to these enzyme targets.(7) Progress inhibitors into cell models of disease, and in human toxicity and specificity(8) Progress active compounds into animal models of these diseases(9) Advance active candidate-quality compounds into treatment of human and veterinary diseases.