Update of Antitubercular Prodrugs from a Molecular Perspective: Mechanisms of Action, Bioactivation Pathways, and Associated Resistance

Abstract The place of prodrugs in the current antitubercular therapeutic arsenal is preponderant, since two of the four first‐line antitubercular agents, isoniazid (INH) and pyrazinamide (PZA), need to be activated by Mycobacterium tuberculosis before exerting their activity. In addition, six other prodrugs can be found in the second‐ and third‐line therapeutic regimens. The emergence of mycobacterial strains resistant to one or several antitubercular agents is one of the main issues of the antitubercular therapy. In the case of prodrugs, the resistance phenomenon is often related to a mutation in the gene encoding for the activation enzymes, resulting thus in a default of these enzymes that are no more able to activate prodrugs. Consequently, identification of the prodrugs targets and a better understanding of their modes of action and also of their activation mechanisms are of crucial importance. Related to their molecular mechanism of activation, these prodrugs may thus be classified in four categories: activation via oxidation (catalase–peroxidase (KatG) or flavin monooxygenase (EthA) enzymes), condensation (FolP1 and FolC), hydrolysis (by the amidase PncA) and reduction (by the nitroreductase DnD) mechanisms. For each prodrug, these mechanisms are described in details, as well as the mechanism of action of its active metabolite. Finally, the reported resistance related to these mechanisms of activation/action are also addressed in a molecular perspective.