THE MABA GENE FROM THE INHA OPERON OF MYCOBACTERIUM-TUBERCULOSIS ENCODES A 3-KETOACYL REDUCTASE THAT FAILS TO CONFER ISONIAZID RESISTANCE

A target of the anti-tuberculosis drugs isoniazid (INH) and ethionamid e (ETH) has been shown to be an enoyl reductase, encoded by the inhA g ene. The mabA (mycolic acid biosynthesis A) gene is located immediatel y upstream of inhA in Mycobacterium tuberculosis, Mycobacterium bovis and Mycobacterium smegmatis. The MabA protein from M. tuberculosis was expressed in Escherichia coli and shown to have 3-ketoacyl reductase activity, consistent with a role in mycolic acid biosynthesis. In M. s megmatis, inhA and mabA are independently transcribed, but in M, tuber culosis and M. bovis BCG, mabA and inhA constitute a single operon. Se veral INH-ETH-resistant M, tuberculosis clinical isolates contain poin t mutations in the ribosome-binding site of mabA in the mabA-inhA oper on. However, genetic dissection of this operon reveals that the INH-ET H-resistance phenotype is encoded only by inhA, and not by mabA.