New Drug Mechanisms: Bedaquiline

摘要

In this series we draw attention to medicines that have entered the European market with an entirely new mechanism of action. Publication is not to be confused with endorsement of use in clinical practice. Copyright of the images belongs to Leiden University, but use of the images (also available at http://coo.lumc.nl/trc and in the app stores) is free.Introduction Tuberculosis (TB) is typically caused by Mycobacterium tuberculosis, a pathogen which usually infects the lungs [1]. The incidence of strains that are resistant to first line TB treatment has increased in the last two decades. Consequently, there is a high medical need for novel new tuberculosis drugs [2]. Mechanism Bedaquiline is the first drug on the market to target the mycobacterial ATP synthase. The production of ATP by the enzyme ATP synthase is crucial for cell survival of both prokaryotic and eukaryotic cells [2]. ATP synthase consists of a transmembrane (F0) and a cytoplasmic (F1) domain [3]. Proton flow through the F0 domain leads to a rotation of the c and γ subunits of the F1 domain. This rotation drives ATP synthesis at the α3β3 hexamer (Figure 1, [4]). The main binding site of bedaquiline is located between the a and c subunits of the F0 domain, near amino acid residue Glu61 [3-5]. Upon binding, bedaquiline inhibits ATP synthesis by blocking the proton flow and the subsequent conformational changes. This causes cell death in both replicating and non-replicating mycobacteria, making bedaquiline a bactericidal antibiotic (Figure 2, [6]). Bedaquiline is selective towards mycobacterial ATP synthase, compared with the human homologue, despite high similarity in protein sequence [7] Indication Bedaquiline has been granted market authorization for the treatment of tuberculosis [1].The current indication covers its use as part of a combination regimen to treat pulmonary multidrug-resistant tuberculosis (MDR-TB) [6].