INHIBITORS OF BRANCHED-CHAIN AMINO-ACID BIOSYNTHESIS AS POTENTIAL ANTITUBERCULOSIS AGENTS

Leucine auxotrophs of Mycobacterium bovis (BCG) were found to have a r educed ability to survive in spleens and lungs of mice. This indicated that inhibitors of branched-chain amino acid biosynthesis could possi bly be used as antituberculosis agents. Herbicides that inhibit plant branched-chain amino acid biosynthetic enzymes were tested for inhibit ion of Mycobacterium tuberculosis growth in vitro. Sulphometuron methy l (SU) and metsulphuron methyl, inhibitors of acetolactate synthase (A LS), had a modest effect on growth of M. tuberculosis strain ATCC 3580 1 (inhibitory concentrations <20 mu M). Two inhibitors of ketol acid r eductoisomerase (KARI) were ineffective against growth of strain ATCC 35801 in vitro. On the other hand, ALS and KARI inhibitors were more e ffective against growth of clinical drug-resistant isolates than again st strain ATCC 35801. Mouse model studies of tuberculosis infection sh owed that high doses of SM significantly prevented growth of M. tuberc ulosis strain ATCC 35801 in the lungs but did not affect the revel of infection in the spleen. The results suggest that inhibitors of branch ed-chain amino acid biosynthesis may be useful as new antituberculosis agents.