Fig. 3. Anti-tuberculosis drug candidate pipeline and mechanism of drug action.

a | Shown are promising drug candidates currently in preclinical and clinical development, including the development of regimens that combine repurposed, repositioned and new drug classes. Approved drugs are indicated by an asterisk (delamanid was approved by the EMA only, and pretomanid was approved by the FDA for use in the bedaquiline–pretomanid–linezolid regimen). Drugs are colour coded by chemical class and target pathway. For a complete list of published candidates currently in the pipeline, from early preclinical development to regulatory approval, and a review of their mechanism of action, see Working Group on New TB Drugs and ref.¹⁸³. b | A simplified version of the cell envelope and the cytoplasmic membrane of Mycobacterium tuberculosis is shown with schematized versions of the targets of recently approved drugs and clinical candidates, with novel mechanisms of action, listed in part a. The majority of novel targets are membrane associated. The diarylquinolines bedaquiline, TBAJ-876 and TBAJ-587 target the ATP synthase. The nitroimidazoles pretomanid and delamanid exhibit a dual mode of action under low and normal oxygen tension, poison multiple essential pathways, and are bactericidal against replicating and non-replicating mycobacteria¹⁸⁴. SQ109 and the MPL series are the most advanced among a broad panel of agents targeting MmpL3, involved in export of trehalose monomycolate, a mycolic acid component. Three chemically distinct series all target DprE1: OPC167832, TBA7371 and BTZ043 (ref.¹⁸⁵). Both MmpL3 and DprE1 are unique to mycobacteria. GSK656 is the first oxaborole in clinical development targeting a mycobacterial tRNA synthetase¹⁸⁶ and GSK286 is a new chemical entity with a novel mechanism of action related to cholesterol catabolism. Part b adapted from ref.¹⁸⁷, Springer Nature Limited.