“Old” molecules and targets represent attractive start points.

Modern medicinal chemistry is essential to convert a compound hit into a drug.

Nutritional flexibility makes inhibition of single-nutrient metabolism fail prone.

Cell-envelope permeability represents a significant hurdle for small molecules.

Mycobacterial “eNRTy” rules would accelerate antitubercular drug discovery.

Tuberculosis (TB) persists as a major global health issue and a leading cause of death by a single infectious agent. The global burden of TB is further exacerbated by the continuing emergence and dissemination of strains of Mycobacterium tuberculosis resistant to multiple antibiotics. The need for novel drugs that can be used to shorten the course for current TB drug regimens as well as combat the persistent threat of antibiotic resistance has never been greater. There have been significant advances in the discovery of de novo TB treatments, with the first TB-specific drugs in 45 years approved for use. However, there are still issues that restrict the pipeline of new antitubercular chemotherapies. The rate of failure of TB drug candidates in clinical trials remains high, while the validation of new TB drug targets and subsequent identification of novel inhibitors remains modest.

© 2022 The Author(s). Published by Elsevier Ltd.