Inhibitors of branched-chain amino acid biosynthesis as potential antituberculosis agents.
Leucine auxotrophs of Mycobacterium bovis (BCG) were found to have a reduced ability to survive in spleens and lungs of mice. This indicated that inhibitors of branched-chain amino acid biosynthesis could possibly be used as antituberculosis agents. Herbicides that inhibit plant branched-chain amino acid biosynthetic enzymes were tested for inhibition of Mycobacterium tuberculosis growth in vitro. Sulphometuron methyl (SM) and metsulphuron methyl, inhibitors of acetolactate synthase (ALS), had a modest effect on growth of M. tuberculosis strain ATCC 35801 (inhibitory concentrations <20 microM). Two inhibitors of ketol acid reductoisomerase (KARI) were ineffective against growth of strain ATCC 35801 in vitro. On the other hand, ALS and KARI inhibitors were more effective against growth of clinical drug-resistant isolates than against strain ATCC 35801. Mouse model studies of tuberculosis infection showed that high doses of SM significantly prevented growth of M. tuberculosis strain ATCC 35801 in the lungs but did not affect the level of infection in the spleen. The results suggest that inhibitors of branched-chain amino acid biosynthesis may be useful as new antituberculosis agents.
Grandoni
J A
JA
Department of Molecular Biology, University of Medicine and Dentistry of New Jersey, Stratford 08084, USA. grandoni@fiam.net
Marta
P T
PT
Schloss
J V
JV
D000095:Acetolactate Synthase / Q000037:antagonists & inhibitors; D000429:Alcohol Oxidoreductases / Q000037:antagonists & inhibitors; D000597:Amino Acids, Branched-Chain / Q000037:antagonists & inhibitors*; D000818:Animals; D000995:Antitubercular Agents / Q000494:pharmacology* / Q000633:toxicity; D015169:Colony Count, Microbial; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000633:toxicity; D006540:Herbicides / Q000494:pharmacology* / Q000633:toxicity; D050540:Ketol-Acid Reductoisomerase; D008168:Lung / Q000187:drug effects / Q000382:microbiology; D051379:Mice; D008826:Microbial Sensitivity Tests; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000254:growth & development; D013154:Spleen / Q000187:drug effects / Q000382:microbiology; D014376:Tuberculosis / Q000382:microbiology / Q000517:prevention & control
D000597:Amino Acids, Branched-Chain; D000995:Antitubercular Agents; D004791:Enzyme Inhibitors; D006540:Herbicides; D000429:Alcohol Oxidoreductases; D050540:Ketol-Acid Reductoisomerase; D000095:Acetolactate Synthase