Novel and revisited approaches in antituberculosis drug discovery

- Bedaquiline and delamanid are the first new approved TB drugs in decades.
- Novel lead structures for TB drugs are needed despite these successes.
- Host-cell based screening can deliver hits with high translational potential.
- Revisiting of existing drugs and neglected antibiotics yielded TB lead structures.
- Natural products are chemically diverse and often exhibit new modes of action.

The increasing prevalence of multidrug-resistant Mycobacterium tuberculosis (Mtb) necessitates the discovery and development of novel drugs against tuberculosis. In this review, we focus on two recent approaches that led to the discovery of promising antitubercular compound classes: (I) Hits derived from large compound library screens are increasingly difficult to translate into clinical application; this in turn fostered the development of innovative screening methods. (II) An alternative strategy towards high-quality hits and leads is to evaluate chemically diverse scaffolds which can be found among natural products. The so-called rekindling and repurposing approaches were particularly fruitful in the last few years.

138Image source (SEM of Mtb): NIAID.