The mechanism by which two small molecules work against the bacterium mycobacterium tuberculosis (Mtb) has been deciphered at a laboratory by scientists at the Indian Institute of Science. These molecules, imipramine and norclomipramine, are not routinely used antibacterials — they are in fact antidepressants.
TB claims approximately 2 million lives on a global scale annually. Treatment for tuberculosis is typically very long, extending anywhere between 6 months to two years; patients sometimes stop following the treatment regimen without finishing it. The problem is compounded by “superbugs” like multidrug and extremely drug resistant TB.
The advance online version of the paper appeared in antimicrobial agents and chemotherapy last month.
In this paper, two related molecules — imipramine and norclomipramine — were shown to inhibitthe enzyme topoisomerase I from Mtb. Imipramine is a tricyclic anti-depressant while norclomipramine is a secondary metabolite of another anti-depressant, clomipramine.
Collaborators including Adwait Godbole and V Nagaraja from department of microbiology and cell biology at IISc have established the mechanism by which these molecules act. In the presence of the enzyme, the compounds were found to stimulate the formation of breaks in the DNA, which are toxic to the bacterial cells. Testing of these molecules on mycobacterial cells showed that they were able to induce cell death, possibly due to formation of breaks in the cellular DNA.
“Their activity against Mtb cells may facilitate further development of novel anti-TB agents,”said Valakunja Nagaraja one of the authors.