PUBLICATION
Supramolecular strategy for reducing the cardiotoxicity of bedaquiline without compromising its antimycobacterial efficacy
- Authors
- Kuok, K.I., In Ng, P.C., Ji, X., Wang, C., Yew, W.W., Chan, D.P.C., Zheng, J., Lee, S.M.Y., Wang, R.
- ID
- ZDB-PUB-171221-3
- Date
- 2017
- Source
- Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association 119: 425-429 (Journal)
- Registered Authors
- Keywords
- Antimycobacterial, Bedaquiline, Cardiotoxicity, Cucurbit[7]uril, Supramolecular formulation
- MeSH Terms
-
- Heart/drug effects*
- Imidazoles/pharmacology
- Chromatography, High Pressure Liquid
- Mycobacterium smegmatis/drug effects
- Zebrafish/embryology
- Tuberculosis, Multidrug-Resistant/drug therapy*
- Bridged-Ring Compounds/pharmacology
- Antitubercular Agents/therapeutic use*
- Solubility
- Diarylquinolines/toxicity*
- Animals, Genetically Modified
- Animals
- Microbial Sensitivity Tests
- PubMed
- 29258954 Full text @ Food Chem. Toxicol.
- CTD
- 29258954
Citation
Kuok, K.I., In Ng, P.C., Ji, X., Wang, C., Yew, W.W., Chan, D.P.C., Zheng, J., Lee, S.M.Y., Wang, R. (2017) Supramolecular strategy for reducing the cardiotoxicity of bedaquiline without compromising its antimycobacterial efficacy. Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association. 119:425-429.
Abstract
Bedaquiline (BDQ) is a newly approved anti-tuberculosis drug in treating multidrug-resistant tuberculosis. However, it has very poor aqueous solubility and several case reports have proposed that BDQ has potential risk of cardiotoxicity to patients. In this present study, we have explored into employing host-guest interactions between a synthetic receptor, cucurbit[7]uril (CB[7]), and BDQ aiming to improve the solubility and reduce the inherent cardiotoxicity of BDQ. HPLC-UV test on the solubility of BDQ in the absence and in the presence of increasing concentrations of CB[7] suggested a host-dependent guest-solubility enhancements. Cardiovascular studies using an in vivo zebrafish model demonstrated that the cardiotoxicity of BDQ was indeed alleviated upon its complexations by the synthetic receptor. Furthermore, our in vitro antibacterial studies suggested that CB[7] formulated BDQ preserved its antimycobacterial efficacy against Mycobacterium smegmatis. Therefore, CB[7] may become a suitable pharmaceutical excipient in formulating BDQ for improving its physiochemical properties (such as solubility), and for alleviating its side effects (such as cardiotoxicity), while the antimycobacterial efficacy of BDQ may be well maintained.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping