β-CA-specific inhibitor dithiocarbamate Fc14–584B: a novel antimycobacterial agent with potential to treat drug-resistant tuberculosis.

Inhibition of novel biological pathways inMycobacterium tuberculosis(Mtb) creates the potential for alternative approaches for treating drug-resistant tuberculosis.In vitrostudies 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 thein vivoinhibitory effect of the least toxic inhibitor onM. marinumin 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 vitroinhibition ofM. marinumshowed that both compounds inhibited growth at a concentration of 75 µM.In vivoinhibition 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. [ABSTRACT FROM PUBLISHER]