Isoniazid (isonicotinic acid hydrazide, INH) has been a first-line effective chemotherapeutic in the treatment of tuberculosis since the early 1950's. In recent years, the more omnious reports of multi-drug resistance strains of M. tuberculosis, and the resulting death of numerous individuals from infections with these strains, has gained national attention. The reality of a presently untreatable disease caused by the appearance of the multi-drug resistant phenotypes has encouraged this effort to describe the biochemical and structural basis of INH resistance. To this end, we have chosen the mycolic acid biosynthetic pathway, not only due to its absence in the host, but also due to the recent determination that the primary protein target for INH action is involved in mycolate biosynthesis. This information will be used to facilitate anti-tubercular drug design through two different approaches. Initially, compounds which structurally resemble isoniazid will be designed with the prospect of offsetting resistance. Secondly, enzymes in the mycolic acid pathway will be targeted for the design of new drugs. To accomplish these goals, we will determine the structure and function of key enzymes in mycolic acid biosynthesis (InhA, MabA) as well as enzymes that have been demonstrated to be involved in INH action (catalase, InhS, InhA).
