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New Drug Approvals 2012 - Pt. XXXII - Bedaquiline (SirturoTM)

ATC Code: J04AK05
Wikipedia: Bedaquiline

On December 28, the FDA approved Bedaquiline (as the fumarate salt; tradename: Sirturo; Research Code: R-403323 (for Bedaquiline Fumarate), R-207910 and TMC-207 (for Bedaquiline)), a novel, first-in-class diarylquinoline antimycobacterial drug indicated for the treatment of pulmonary multi-drug resistant tuberculosis (MDR-TB) as part of combination therapy in adults.

Turbeculosis is an infectious disease caused by the mycobacteria Mycobacterium tuberculosis, which usually affects the lungs. MDR-TB occurs when M. tuberculosis becomes resistant to the two most powerful first-line treatment anti-TB drugs, Isoniazid (ChEMBL: CHEMBL64) and Rifampin (ChEMBL: CHEMBL374478). Bedaquiline is the first anti-TB drug that works by inhibiting mycobacterial adenosine 5'-triphosphate (ATP) synthase (for Uniprot_IDs, clique here), an enzyme essential for the replication of the mycobacteria.

ATP is the most commonly used energy currency of cells for most organisms. ATP synthase produces ATP from adenosine phosphate (ADP) and inorganic phosphate using energy from a transmembrane proton-motive force generated by respiration. The image above depicts a model of the mycobacterial ATP synthase. ATP synthase has two major structural domains, F0 and F1, that act as a biological rotary motor. The F1 domain is composed of subunits α3 (Uniprot: P63673), β3 (Uniprot: P63677), γ3 (Uniprot: P63671), δ and ε (Uniprot: P63662); the F0 domain includes one a subunit (Uniprot: P63654), two b subunits (Uniprot: P63656) and 9 to 12 c subunits (Uniprot: P63691) arranged in a symmetrical disk. The F0 and F1 domains are linked by central stalks (subunits γ and ε) and peripheral stalks (subunits b and δ). The proton-motive force fuels the rotation of the transmembrane disk and the central stalk, which in turn modulates the nucleotide affinity in the catalytic β subunit, leading to the production of ATP.

It has been shown that mutation in the atpE gene, which encodes the c subunit, of the mycobacterial ATP synthase, confers resistant to Bedaquiline, suggesting that Bedaquiline binds crucially to this target (although almost certainly other components of the complex are required for a competent binding site), inhibiting the proton pump of M. tuberculosis and therefore interfering with the rotation properties of the transmembrane disk, leading to ATP depletion.
>ATPL_MYCTU ATP synthase subunit c
Another notable feature is the high specificity of Bedaquiline for mycobacteria. This is due to the fact that there is very limited sequence similarity between the mycobacterial and human atpE proteins.

Bedaquiline is a diarylquinoline antimycobacterial drug, which displays both planar hydrophobic moieties and hydrogen-bonding acceptor and donor groups. It has a molecular weight of 555.50 Da (671.58 for the fumarate salt), an ALogP of 6.93, 4 hydrogen-bond acceptors and 1 hydrogen-bond donor, and therefore not fully rule-of-five compliant.

Name: (1R, 2S)-1-(6-bromo-2­ methoxy-3-quinolinyl)-4-(dimethylamino)-2-(1-naphthalenyl)-1-phenyl-2-butanol
Canonical Smiles: COc1nc2ccc(Br)cc2cc1[C@@H](c3ccccc3)[C@@](O)(CCN(C)C)c4cccc5ccccc45
InChI: InChI=1S/C32H31BrN2O2/c1-35(2)19-18-32(36,28-15-9-13-22-10-7-8-14-26(22)28)30(23-11-5-4-6-12-23)27-21-24-20-25(33)16-17-29(24)34-31(27)37-3/h4-17,20-21,30,36H,18-19H2,1-3H3/t30-,32-/m1/s1

The recommended dosage of Bedaquiline is 400 mg once daily for 2 weeks followed by 200 mg 3 times per week for 22 weeks with food.

Bedaquiline shows a volume of distribution of approximately 164 L and a plasma binding protein of > 99.9%. Bedaquiline is primarily subjected to oxidative metabolism by CYP3A4 leading to the formation of the N-monodesmethyl metabolite (M2), which is 4 to 6 times less active in terms of antimycobacterial potency. It is mainly eliminated in feces and the mean terminal half-life T1/2 of Bedaquiline and M2 is approximately 5.5 months.

The license holder is Janssen Therapeutics and the full prescribing information of Bedaquiline can be found here.



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