Bedaquiline: Fallible Hope Against Drug Resistant Tuberculosis

Abstract

Tuberculosis (TB) is a deadly bacterial infectious disease caused by intra-cellular pathogen Mycobacterium tuberculosis (Mtb). There were an estimated 1.4 million TB deaths in 2015 and an additional 0.4 million deaths resulting from TB among individuals with HIV. Drug-discovery for its cure is very slow in comparison with the causative organism's fast pace of mutations conferring drug resistance. Moreover, the field of drug-discovery of anti-TB drugs is constantly being challenged by the drug resistant strains of Mtb. Several molecules/inhibitors are being tested across the pharmaceutical industry and research centres for their suitability as drug candidate. It takes immense effort, high costs and a whole lot of screening to bring a single molecule to the clinics for patient cure. In last 60 years, hundreds of molecules have been patented for their probable use to develop drug for treatment of TB. However, only one drug has been successfully approved that is bedaquiline (1-(6-bromo-2 -methoxy-quinolin-3-yl)-4-dimethylamino-2-naphtalen-1-yl-1-phenyl-butan-2-ol). This is a brief review about bedaquiline (BDQ), the only drug in last 45 years approved for curing drug-resistant pulmonary TB, its development, action mechanism and development of resistance against it.

Keywords: Bedaquiline (Sirturo); Diarylquinoline; Drug-resistance; Mycobacterium; Tuberculosis (TB).

Fig. 1

Diagrammatic representation of the classification of the tuberculosis based on the type of resistance in the M. tuberculosis strains causing the TB infection

Fig. 2

a Chemical structure of BDQ, b slanted view of the ion-binding side showing the interaction of BDQ with the c-ring and Two-dimensional (2D) plot of the BDQ/c-ring interactions. (figure courtesy: Laura Preiss et al. Sci Adv 2015;1:e1500106) and c diagrammatic representation and depiction of the drug resistance mutations in mycobacterial ATP synthase (figure courtesy: http://chembl.blogspot.in/2013/01/)