Bedaquiline fumarate

Biological Activity

Bedaquiline inhibits the growth of TDR M. tuberculosis strains, with MIC values ranging from 0.125 to 0.5 mg/L. Among slowly growing mycobacteria (SGM), bedaquiline exhibits the highest activity against Mycobacterium avium with MIC50 and MIC90 values of 0.03 and 16 mg/L, respectively. Among rapidly growing mycobacteria (RGM), Mycobacterium abscessus subsp. abscessus (M. abscessus) and Mycobacterium abscessus subsp. massiliense (M. massiliense) seem more susceptible to bedaquiline than Mycobacterium fortuitum, with MIC50 and MIC90 values of 0.13 and >16 mg/L, respectively, for both species. Bedaquiline also shows moderate in vitro activity against NTM species. Bedaquiline has an excellent in vitro activity against Mycobacterium tuberculosis, including multidrug resistant M tuberculosis.

Protocol

Cell Experiment
Cell lines	M. tuberculosis
Preparation method	M. tuberculosis was cultured in 7H9 broth and grown to an A600 nm of 0.8. Cultures were treated with 0.1, 1 or 10 mg ml 1 BDQ for 24 h. NADH and NAD þ concentrations were determined and the NADH/NAD þ ratio was calculated as described.
Concentrations	0.1, 1 and 10 mg/ml
Incubation time	24 h

Animal Experiment
Animal models	BALB/c mice
Formulation
Dosages	25 mg/kg
Administration	i.v.

Conversion of different model animals based on BSA (Value based on data from FDA Draft Guidelines)

Species	Mouse	Rat	Rabbit	Guinea pig	Hamster	Dog
Weight (kg)	0.02	0.15	1.8	0.4	0.08	10
Body Surface Area (m2)	0.007	0.025	0.15	0.05	0.02	0.5
Km factor	3	6	12	8	5	20

Animal A (mg/kg) = Animal B (mg/kg) multiplied by	Animal B Km
	Animal A Km

For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the K_m factor for a mouse and then divide by the K_m factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.

Chemical Information

References

Verapamil increases the bactericidal activity of bedaquiline against Mycobacterium tuberculosis in a mouse model.
Gupta S, et al. Antimicrob Agents Chemother. 2015 Jan;59(1):673-6. PMID: 25331694.

Delayed bactericidal response of Mycobacterium tuberculosis to bedaquiline involves remodelling of bacterial metabolism
A Koul, et al. Nat Commun. 2014 Feb 26;5:3369. PMID: 24569628.