The mechanism by which two small molecules work against the bacterium Mycobacterium tuberculosis (Mtb) has been deciphered at a laboratory in IISc. These molecules, imipramine and norclomipramine, are not routinely used antibacterials – they are in fact antidepressants and their derivatives!
Mtbis the bacterium that causes the dreaded disease, tuberculosis (TB). 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. A co-occurrence of AIDS and TB further worsens the situation.
Given all these factors, a therapeutic method that can target essential proteins in the pathogen is the need of the hour. “More Medicines for TB” (MM4TB) is an international consortium that has been assembled by the EU to discover new treatment methods to combat the global health issue. Among the many approaches and strategies of the consortium, one is to screen small molecules (including FDA approved) against vital proteins in Mtb. Topoisomerase I is one such essential protein, which is involved in winding and unwinding of the bacterial DNA.
In this paper, two related molecules -- imipramine and norclomipramine -- were shown to inhibit the 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 Prof 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. These results illustrate the possibility to repurpose known drugs that are not known earlier to be anti-bacterials as potential agents against Mtb.
About the authors
Adwait Anand Godbole, Wareed Ahmed, Rajeshwari Subray Bhat and Valakunja Nagaraja are at the Department of Microbiology and Cell Biology, Indian Institute of Science, Bangalore, India. Collaborator Erin K. Bradley is with LigDCipher, San Mateo, California, USA and Sean Ekins with Collaborative Drug Discovery, Burlingame, California, USA.
Valakunja Nagaraja: firstname.lastname@example.org
Adwait Anand Godbole: email@example.com
The advance online version of the paper appeared in Antimicrobial Agents and Chemotherapy in December 2014. http://aac.asm.org/content/early/2014/12/16/AAC.04516-14