Title:Multifunctional Enzymes as Targets for the Treatment of Tuberculosis: Paving the Way for New Anti-TB Drugs
Volume: 28
Issue: 28
Author(s): Carla Sílvia Silva Teixeira, Nuno M.F.S.A. Cerqueira and Sérgio Filipe Sousa*
Affiliation:
- UCIBIO@REQUIMTE, BioSIM, Departamento de Biomedicina da Faculdade de Medicina da Universidade do Porto, Alameda Professor Hernâni Monteiro, 4200-319, Porto,Portugal
Keywords:
Tuberculosis, drug targets, multifunctional enzymes, purine biosynthesis, co-factor biosynthesis, amino
acid biosynthesis.
Abstract: In spite of the medical and technological developments of the last centuries,
Tuberculosis (TB) has remained a challenging disease, with a limited number of therapeutic
options, particularly in light of the increase in drug-resistant cases. The search for new
molecules continues, with several candidates currently in clinical testing and ongoing efforts
to identify novel targets. This work summarizes recent developments on anti-TB
therapy, starting by discussing the current epidemiologic status and presenting an
overview of the history of anti-tuberculosis drug discovery. Special attention is dedicated
to five multifunctional enzymes that are regarded as promising targets for new anti-TB
drugs: 5-aminoimidazole-4-carboxamide ribonucleotide transformylase/IMP cyclohydrolase
(ATIC); 3,4-dihydroxy-2-butanone 4-phosphate synthase (DHBPS)/GTP cyclohydrolase
II (GCHII); glutamine dependent NAD+ Synthetase (NadE); chorismate synthase (CS);
and Tryptophan synthase (TS). These enzymes are involved in metabolic pathways
critical for the M. tuberculosis survival, growth or replication, but that are not expressed
in humans or have significant differences in terms of functionality, which makes them appealing
targets. Their function, structure, possible catalytic mechanisms, and current inhibition
strategies and inhibitors are reviewed and discussed.
