A proof-of-concept study has successfully identified two small molecules (imipramine and norclomipramine) that can arrest the growth of TB bacteria and hence have the potential to be used as anti-TB drugs once the chemical properties are altered to make it more effective.
Interestingly, one of the small molecules (imipramine) is already in clinical use as an antidepressant while other is a metabolite of antidepressant clomipramine. But, they have never been used as antibacterials.
The two small molecules work by targeting the Topoisomerase I enzyme of the TB bacteria. This enzyme is essential for controlling the coiling (winding) and uncoiling (unwinding) of the bacterial DNA. The results of the study were published recently in the journal Antimicrobial Agents and Chemotherapy.
“We have for the first time found inhibitors that prevent the enzyme from functioning. The inhibition of the enzyme arrests the growth/division of the bacteria and eventually causes death,” Prof. V. Nagaraja of the Department of Microbiology and Cell Biology, Indian Institute of Science (IISc), Bengaluru and the senior author of the paper told this Correspondent. He led the team that identified the inhibitors.
Though the two molecules inhibited cell growth by preventing DNA coiling, the potency was not high enough. “The inhibition is not as effective as drugs that are already being used as anti-TB drugs,” he said.
He has been working on this enzyme for a long time. This class of enzyme is found in all bacteria and even in higher organisms like mammals and humans. But human Topoisomerase I enzyme has properties and functions that are very different from that of bacteria. And inhibitors for human Topoisomerase I enzyme have already been identified and successfully exploited, as in the case of cancer drugs. “But there has been no such progress in the case of bacteria, as inhibitors of bacterial Topoisomerase I enzyme were not identified so far,” Prof. Nagaraja said.
Even in the case of bacterial Topoisomerase II enzyme, inhibitors have long been identified and clinically-validated drugs such as ciprofloxacin and other members of the fluoroquinolones are widely in use today. Since the small molecules studied are being routinely used as antidepressants, it may not be possible to use them as anti-TB drugs in the current form.
However, small changes in the chemical entity of the molecules can change the properties and activities dramatically. “This has to be done in this case,” he said. “The current study only highlights the potential of repurposing or redesigning existing drugs that are not antibacterials as anit-TB drugs.”
As no X-ray crystal structure and, hence, atomic details of the enzyme is available, a 3D structure of the enzyme was modeled by the co-author Dr. Sean Ekins of Collaborative Drug Discovery, a company based in California.
The molecules that can be likely candidates were first identified through virtual screening of many compound libraries. Further studies were then carried out in the laboratory of Prof. Nagaraja to find their inhibiting properties.
The identification of the two small molecules was part of the TB consortium project “More Medicine for TB’s” (MM4TB) with the larger goal of screening small molecules as potential anti-TB drugs. The MM4TB is an international consortium that has been assembled by the EU to discover new treatment methods to combat TB.