The pipeline of new molecules and regimens against drug-resistant tuberculosis.

The clinical development and regulatory approval of bedaquiline, delamanid and pretomanid over the last decade brought about significant progress in the management of drug-resistant tuberculosis, providing all-oral regimens with favorable safety profiles. The Nix-TB and ZeNix trials of a bedaquiline - pretomanid - linezolid regimen demonstrated for the first time that certain forms of drug-resistant tuberculosis can be cured in the majority of patients within 6 months. Ongoing Phase 3 studies containing these drugs may further advance optimized regimen compositions. Investigational drugs in clinical development that target clinically validated mechanisms, such as second generation oxazolidinones (sutezolid, delpazolid, TBI-223) and diarylquinolines (TBAJ-876 and TBAJ-587) promise improved potency and/or safety compared to the first-in-class drugs. Compounds with novel targets involved in diverse bacterial functions such as cell wall synthesis (DrpE1, MmpL3), electron transport, DNA synthesis (GyrB), cholesterol metabolism and transcriptional regulation of ethionamide bioactivation pathways have advanced to early clinical studies with the potential to enhance antibacterial activity when added to new or established anti-TB drug regimens. Clinical validation of preclinical and animal model predictions of new anti-TB regimens may further improve the translational value of these models to identify optimal anti-TB therapies.