Project: Research project

Project Details


Tuberculosis remains the largest cause of death in the world from a
single infectious disease and is responsible for one in four avoidable
adult deaths in developing countries. Infection with drug-sensitive
strains of Mycobacterium tuberculosis can be effectively cured with a
combination of isoniazid (INH), rifampicin, and pyrazinamide. However,
the emergence of multiple drug resistant strains of M. tuberculosis has
resulted in fatal outbreaks in the United States. INH was first reported
to be active against M. tuberculosis in 1952, when it was shown to have
a highly specific activity against M. tuberculosis and M bovis with less
but considerable activity against other mycobacteria. Although INH is
one of the most widely used anti-tuberculosis drugs for both therapy and
prophylaxis, its precise target of action on Mycobacterium tuberculosis
is unknown. We have discovered a novel gene, named inhA, in M.
tuberculosis and all mycobacterial species examined that encodes a target
for both isoniazid and ethionamide. The inhA gene encodes a protein of
32 kDa that shows significant sequence conservation with an E. coli
enzyme, EnvM, known to play a role in fatty acid biosynthesis. Cell-free
assays indicate the involvement of InhA protein in mycolic acid
biosynthesis, previously suggested site of action of INH. In this
proposal, we intend to employ a combination of genetic, biochemical, and
x-ray crystallographic methods to characterize the InhA protein and
elucidate mechanism of inhibition by ethionamide and isoniazid.
Effective start/end date8/1/944/30/98


  • Medicine(all)
  • Immunology and Microbiology(all)