Biomaterial Database

Inhibitors of branched-chain amino acid biosynthesis as potential antituberculosis agents. 1998

J A Grandoni, and P T Marta, and J V Schloss

Department of Molecular Biology, University of Medicine and Dentistry of New Jersey, Stratford 08084, USA. grandoni@fiam.net

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.

UI	MeSH Term	Description	Entries
D008168	Lung	Either of the pair of organs occupying the cavity of the thorax that effect the aeration of the blood.	Lungs
D008826	Microbial Sensitivity Tests	Any tests that demonstrate the relative efficacy of different chemotherapeutic agents against specific microorganisms (i.e., bacteria, fungi, viruses).	Bacterial Sensitivity Tests,Drug Sensitivity Assay, Microbial,Minimum Inhibitory Concentration,Antibacterial Susceptibility Breakpoint Determination,Antibiogram,Antimicrobial Susceptibility Breakpoint Determination,Bacterial Sensitivity Test,Breakpoint Determination, Antibacterial Susceptibility,Breakpoint Determination, Antimicrobial Susceptibility,Fungal Drug Sensitivity Tests,Fungus Drug Sensitivity Tests,Sensitivity Test, Bacterial,Sensitivity Tests, Bacterial,Test, Bacterial Sensitivity,Tests, Bacterial Sensitivity,Viral Drug Sensitivity Tests,Virus Drug Sensitivity Tests,Antibiograms,Concentration, Minimum Inhibitory,Concentrations, Minimum Inhibitory,Inhibitory Concentration, Minimum,Inhibitory Concentrations, Minimum,Microbial Sensitivity Test,Minimum Inhibitory Concentrations,Sensitivity Test, Microbial,Sensitivity Tests, Microbial,Test, Microbial Sensitivity,Tests, Microbial Sensitivity
D009169	Mycobacterium tuberculosis	A species of gram-positive, aerobic bacteria that produces TUBERCULOSIS in humans, other primates, CATTLE; DOGS; and some other animals which have contact with humans. Growth tends to be in serpentine, cordlike masses in which the bacilli show a parallel orientation.	Mycobacterium tuberculosis H37Rv
D004791	Enzyme Inhibitors	Compounds or agents that combine with an enzyme in such a manner as to prevent the normal substrate-enzyme combination and the catalytic reaction.	Enzyme Inhibitor,Inhibitor, Enzyme,Inhibitors, Enzyme
D006540	Herbicides	Pesticides used to destroy unwanted vegetation, especially various types of weeds, grasses (POACEAE), and woody plants. Some plants develop HERBICIDE RESISTANCE.	Algaecide,Algicide,Herbicide,Algaecides,Algicides
D000095	Acetolactate Synthase	A flavoprotein enzyme that catalyzes the formation of acetolactate from 2 moles of PYRUVATE in the biosynthesis of VALINE and the formation of acetohydroxybutyrate from pyruvate and alpha-ketobutyrate in the biosynthesis of ISOLEUCINE. This enzyme was formerly listed as EC 4.1.3.18.	Acetohydroxy Acid Synthase,Acetohydroxy Acid Synthetase,Acetolactate Synthetase,Acetohydroxyacid Synthetase I,Acetoxyhydroxyacid Synthase III,Acid Synthase, Acetohydroxy,Acid Synthetase, Acetohydroxy,Synthase III, Acetoxyhydroxyacid,Synthase, Acetohydroxy Acid,Synthase, Acetolactate,Synthetase I, Acetohydroxyacid,Synthetase, Acetohydroxy Acid,Synthetase, Acetolactate
D000429	Alcohol Oxidoreductases	A subclass of enzymes which includes all dehydrogenases acting on primary and secondary alcohols as well as hemiacetals. They are further classified according to the acceptor which can be NAD+ or NADP+ (subclass 1.1.1), cytochrome (1.1.2), oxygen (1.1.3), quinone (1.1.5), or another acceptor (1.1.99).	Carbonyl Reductase,Ketone Reductase,Carbonyl Reductases,Ketone Reductases,Oxidoreductases, Alcohol,Reductase, Carbonyl,Reductase, Ketone,Reductases, Carbonyl,Reductases, Ketone
D000597	Amino Acids, Branched-Chain	Amino acids which have a branched carbon chain.	Branched-Chain Amino Acid,Amino Acids, Branched Chain,Acid, Branched-Chain Amino,Acids, Branched-Chain Amino,Amino Acid, Branched-Chain,Branched Chain Amino Acid,Branched-Chain Amino Acids
D000818	Animals	Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA.	Animal,Metazoa,Animalia
D000995	Antitubercular Agents	Drugs used in the treatment of tuberculosis. They are divided into two main classes: "first-line" agents, those with the greatest efficacy and acceptable degrees of toxicity used successfully in the great majority of cases; and "second-line" drugs used in drug-resistant cases or those in which some other patient-related condition has compromised the effectiveness of primary therapy.	Anti-Tuberculosis Agent,Anti-Tuberculosis Agents,Anti-Tuberculosis Drug,Anti-Tuberculosis Drugs,Antitubercular Agent,Antitubercular Drug,Tuberculostatic Agent,Tuberculostatic Agents,Antitubercular Drugs,Agent, Anti-Tuberculosis,Agent, Antitubercular,Agent, Tuberculostatic,Anti Tuberculosis Agent,Anti Tuberculosis Agents,Anti Tuberculosis Drug,Anti Tuberculosis Drugs,Drug, Anti-Tuberculosis,Drug, Antitubercular