Researchers identify target of key TB drugs, reveal enzyme complex structure

An international research team has identified the precise target and mechanism by which pretomanid and delamanid, described as key drugs for tuberculosis treatment, kill the bacterium that causes TB.

Researchers led by Professor Zhang Lu of ShanghaiTech University in China and Professor Gurdyal Besra of the University of Birmingham in the United Kingdom published a study on the structure of the Mycobacterium tuberculosis DprE1-DprE2 enzyme complex on the 2nd in the international journal Nature Chemical Biology.

Using cryo-electron microscopy (cryo-EM), the researchers determined the structures of the Mycobacterium tuberculosis DprE1-DprE2 complex bound to a substrate, quabodepistat, and activated pretomanid and delamanid, respectively.

The complex was bound to the cell membrane in a tetrameric form, with one DprE1 molecule attached to each side of a DprE2 dimer. Both pretomanid and delamanid bound to DprE2 in the form of NADH adducts.

Quabodepistat was found to bind to DprE1 in a distinctive manner. The researchers said the findings reveal how the drugs work and provide a basis for the rational design of new derivatives that could improve TB treatment.

In 2022, tuberculosis was the world's second-leading cause of death from a single infectious agent, after COVID-19. The emergence of multidrug-resistant and extensively drug-resistant TB has made the development of new antituberculosis drugs urgent.

Pretomanid was approved by the U.S. Food and Drug Administration (FDA) in 2019, and delamanid was approved in Europe and Japan in 2014. Both drugs are prodrugs and are activated only by the Ddn enzyme in Mycobacterium tuberculosis.

Quabodepistat is an antituberculosis candidate developed by Japan's Otsuka Pharmaceutical and is currently in clinical trials. The drug inhibits DprE1 and is known to have moderate activity against nontuberculous mycobacteria.

DprE1 and DprE2 are both essential enzymes for the synthesis of arabinogalactan and lipoarabinomannan, key components of the Mycobacterium tuberculosis cell wall. Until now, no structural information on DprE2 was available, and the active metabolite forms of pretomanid and delamanid had not been clearly characterized.

The researchers said the study will provide a foundation for understanding how antituberculosis drugs and drug candidates inhibit DprE1-DprE2.