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The spread of multidrug-resistant isolates of  Mycobacterium tuberculosis  requires the discovery of new drugs directed to new targets. In this study, we investigated the activity of two boldine-derived alkaloids, seconeolitsine (SCN) and  N -methyl-seconeolitsine ( N -SCN), against  M. tuberculosis . These compounds have been shown to target DNA topoisomerase I enzyme and inhibit growth of  Streptococcus pneumoniae . Both SCN and  N -SCN inhibited  M. tuberculosis  growth at 1.95–15.6 μM, depending on the strain. In  M. smegmatis  this inhibitory effect correlated with the amount of topoisomerase I in the cell, hence demonstrating that this enzyme is the target for these alkaloids in mycobacteria. The gene coding for topoisomerase I of strain H37Rv (MtbTopoI) was cloned into pQE1 plasmid of  Escherichia coli . MtbTopoI was overexpressed with an N-terminal 6-His-tag and purified by affinity chromatography.  In vitro  inhibition of MtbTopoI activity by SCN and  N -SCN was tested using a plasmid relaxation assay. Both SCN and  N -SCN inhibited 50% of the enzymatic activity at 5.6 and 8.4 μM, respectively. Cleavage of single-stranded DNA was also inhibited with SCN. The effects on DNA supercoiling were also evaluated  in vivo  in plasmid-containing cultures of  M. tuberculosis . Plasmid supercoiling densities were −0.060 in cells untreated or treated with boldine, and −0.072 in 1 × MIC  N -SCN treated cells, respectively, indicating that the plasmid became hypernegatively supercoiled in the presence of  N -SCN. Altogether, these results demonstrate that the  M. tuberculosis  topoisomerase I enzyme is an attractive drug target, and that SCN and  N -SCN are promising lead compounds for drug development.

Boldine-Derived Alkaloids Inhibit the Activity of DNA Topoisomerase I and Growth of Mycobacterium tuberculosis