Folate pathway inhibitors, an underestimated and underexplored molecular target for new anti-tuberculosis agents

Abstract: The folate metabolic cycle is an important biochemical process for the maintenance of cellular homeostasis, and is a widely studied pathway of cellular replication control in all organisms. In microorganisms such as M. tuberculosis (Mtb), for instance, dihydrofolate reductase (MtDHFR) is the enzyme commonly explored as a molecular target for the development of new antibiotics. In the same way, dihydropteroate synthase (MtDHPS) was studied extensively until the first multidrug-resistant strains of mycobacteria that could not be killed by sulfonamides were found. However, the other enzymes belonging to the metabolic cycle, until recently less explored, have drawn attention as potential molecular targets for obtaining new antituberculosis agents. Recent structural determinations and mechanism of action studies of Mtb flavin-dependent thymidylate synthase (MtFDTS) and MtRv2671, enzymes that acts on alternative metabolic pathways within the folate cycle, have greatly expanded the scope of potential targets that can be screened in drug design process. Despite the crystallographic elucidation of most cycle proteins, some enzymes, such as dihydrofolate synthase (MtDHFS) and serine hydroxylmethyltransferase (MtSHMT), remain underexplored. In this review, we highlight recent efforts towards the inhibitor design to achieve innovative antituberculosis agents and a brief history of all enzymes present in the folate metabolic cycle. In the final section of this work, we have presented the main synthetic strategies used to obtain the most promising inhibitors.