The bacterial world contains a treasure trove of potent compounds with biological activities that can be harnessed for human benefit. Researchers from CSIR-National Chemical Laboratory, Pune and the Jawaharlal Nehru Tropical Botanic Garden and Research Institute, Thiruvananthapuram, have recently found that Urdamycin, a compound produced by Streptomyces bacteria, has the ability to induce cell death in cancer cells.
In a bid to find natural therapeutic routes to cancer treatment, scientists are actively researching novel bioactive chemicals produced by bacteria. Although some such compounds find extensive use in chemotherapy in combination with other drugs, most have limited efficacy and are known to cause side effects.
Their study shows that this bioactive bacterial compound has a better scope as an anti-cancer drug compared to Rapamycin — a drug currently widely used in combination in chemotherapy. The study reveals that Urdamycin not only binds to a critical cell growth protein but also induces tumour cell death in two different ways.
Bacteria live under constant hostility from various environmental factors, including competition from other microbes. To thrive, many of them have developed toxins to ward off invaders, or chemical messengers to carry out social communication within their community. Some higher-order bacteria living in regions of rich biodiversity produce compounds that can have clinical use as drugs. Hence, such bacteria are extensively exploited, one example being the Streptomyces group which produces many bioactive compounds, including one called Rapamycin.
Initially, Rapamycin drew attention as an anti-cancer drug (often used in combination with other chemotherapeutic medications), though its exact mechanism of action remained unknown for many years. About two decades ago, scientists revealed that Rapamycin bound to a critical growth protein called mTOR (mechanistic or mammalian Target of Rapamycin), and thus inhibited tumour cell growth.
Further investigations revealed that mTOR forms a complex of proteins, including two forms — mTORC1 and mTORC2, both of which play important roles in cell growth. However, Rapamycin only binds mTORC1, thereby limiting its ability to induce cancer cell death. Hence, the requirement for more efficient mTOR inhibitors re-emerged and became a significant area of interest.
“In an attempt to discover novel bioactive bacterial compounds, we explored the rich bacterial biodiversity of the Western Ghats,” says Dan. He was instrumental in identifying the bacterial species StreptomycesOA293 that produces Urdamycin.
The process of identifying, extracting and analysing suitable compounds for cancer treatment is an arduous one. Also, it is challenging to synthesise and purify them from bacterial cultures in the laboratory, or to ascertain their molecular structures.
To overcome these difficulties, the team employed a multi-pronged strategy. First, they screened the genetic material of the Streptomyces OA293 by whole-genome analysis. This allowed them to list gene clusters that might be able to produce potential anti-cancer compounds. Then they extracted the pure form of the compounds from the bacteria. The extractions were subjected to rigorous biochemical analysis using Nuclear Magnetic Resonance and Mass Spectrometry, which helped the researchers ascertain the molecular structure of the compounds. Finally, the compounds that showed the greatest potential to inhibit mTOR — Urdamycin V and E — were purified and tested on lab cultures of breast and cervical cancer cells.
Vinodh J S, a team member, says, “Our research reveals that Urdamycin is a more potent mTOR inhibitor than Rapamycin. It completely inactivates both the components mTORC1 and mTORC2.” The study also indicates the possibility that the intracellular binding sites of Urdamycin and Rapamycin are different. Moreover, Urdamycin induces programmed cancer cell death in two ways: by apoptosis (triggering the killing of tumour cells) and by autophagy (triggering starvation of the tumour cells).
“Our study reveals that Urdamycin completely inhibits Akt activation — another signalling protein, known to be involved in tumour progression and cell survival — leading to cancer cell death,” Dastager points out.
“The biochemical approach employed in this study is solid and well-established. The novel method aided in revealing the exact molecular structure of Urdamycin and the mechanism by which it induces cancer cell death,” says Suchetan Pal, assistant professor at the Indian Institute of Technology, Bhilai. He was not involved in the study.
Collectively, the initial results indicate that Urdamycin has potential therapeutic value for cancer treatment and can be scaled up for further analysis, suggests Pal.