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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.
Acknowledgements
We thank Aulikki Lehmus and Marianne Kuuslahti for the skillful technical assistance with most laboratory experiments, Leena Mäkinen and Hannaleena Piippo for the technical assistance with zebrafish experiments, and Laura Kantanen for the help with M. marinum experiments. We also thank Alma Yrjänäinen for the help with immunohistochemistry experiments. We thank Dr. Siouxsie Wiles and Dr. James P. Dalton for their valuable help in mycobacterial transformations.
Disclosure statement
No potential conflict of interest was reported by the authors.