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-aminoimidazole4-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.