PUBLICATION
β-CA-specific inhibitor dithiocarbamate Fc14-584B: a novel antimycobacterial agent with potential to treat drug-resistant tuberculosis
- Authors
- Aspatwar, A., Hammarén, M., Koskinen, S., Luukinen, B., Barker, H., Carta, F., Supuran, C.T., Parikka, M., Parkkila, S.
- ID
- ZDB-PUB-170622-15
- Date
- 2017
- Source
- Journal of enzyme inhibition and medicinal chemistry 32: 832-840 (Journal)
- Registered Authors
- Keywords
- Dithiocarbamates, Mycobacterium marinum, in vivo inhibition, zebrafish embryos, β-carbonic anhydrase
- MeSH Terms
-
- Animals
- Antitubercular Agents/chemical synthesis
- Antitubercular Agents/chemistry
- Antitubercular Agents/pharmacology*
- Carbonic Anhydrase Inhibitors/chemical synthesis
- Carbonic Anhydrase Inhibitors/chemistry
- Carbonic Anhydrase Inhibitors/pharmacology*
- Carbonic Anhydrases/metabolism*
- Dose-Response Relationship, Drug
- Larva/microbiology
- Microbial Sensitivity Tests
- Mycobacterium tuberculosis/drug effects*
- Mycobacterium tuberculosis/enzymology
- Mycobacterium tuberculosis/growth & development
- Piperazines/chemical synthesis
- Piperazines/chemistry
- Piperazines/pharmacology*
- Structure-Activity Relationship
- Thiocarbamates/chemical synthesis
- Thiocarbamates/chemistry
- Thiocarbamates/pharmacology*
- Tuberculosis, Multidrug-Resistant/drug therapy*
- Zebrafish/microbiology
- PubMed
- 28629306 Full text @ J Enzyme Inhib Med Chem
Citation
Aspatwar, A., Hammarén, M., Koskinen, S., Luukinen, B., Barker, H., Carta, F., Supuran, C.T., Parikka, M., Parkkila, S. (2017) β-CA-specific inhibitor dithiocarbamate Fc14-584B: a novel antimycobacterial agent with potential to treat drug-resistant tuberculosis. Journal of enzyme inhibition and medicinal chemistry. 32:832-840.
Abstract
Inhibition of novel biological pathways in Mycobacterium tuberculosis (Mtb) creates the potential for alternative approaches for treating drug-resistant tuberculosis. In vitro studies have shown that dithiocarbamate-derived β-carbonic anhydrase (β-CA) inhibitors Fc14-594 A and Fc14-584B effectively inhibit the activity of Mtb β-CA enzymes. We screened the dithiocarbamates for toxicity, and studied the in vivo inhibitory effect of the least toxic inhibitor on M. marinum in a zebrafish model. In our toxicity screening, Fc14-584B emerged as the least toxic and showed minimal toxicity in 5-day-old larvae at 300 µM concentration. In vitro inhibition of M. marinum showed that both compounds inhibited growth at a concentration of 75 µM. In vivo inhibition studies using 300 µM Fc14-584B showed significant (p > .05) impairment of bacterial growth in zebrafish larvae at 6 days post infection. Our studies highlight the therapeutic potential of Fc14-584B as a β-CA inhibitor against Mtb, and that dithiocarbamate compounds may be developed into potent anti-tuberculosis drugs.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping