GlmU: One Step Closer towards Breaking the Great Wall of Tuberculosis

Dr. Meetu Agarwal and Dr. Vijay Soni’s joint interview with Bio Patrika hosting “Vigyan Patrika”, a series of author interviews. Meetu and Vijay are joint-first authors on the recent research paper “Unique C-terminal extension and interactome of Mycobacterium tuberculosis GlmU impacts its in vivo function and the survival of the pathogen”, published in Biochem J (2021). In this interview, they talk about this work and its relevance in the context of the tuberculosis.

Meetu Agarwal, Ph.D., is currently working as an assistant professor at the department of molecular medicine, Jamia Hamdard University. Dr. Meeetu Agarwal did her Postdoctoral research at the National Institute of Immunology, New Delhi. Dr. Meetu has completed her Ph.D. from Jawaharlal Nehru University (JNU), New Delhi.

Vijay Soni, Ph.D., is currently working as an instructor of microbiology in medicine at Weill Cornell Medical College, New York. Using a microbial metabolomics approach, he is studying drug metabolism in the context of drug-resistant Mycobacterium tuberculosis. Dr. Soni has completed his Ph.D. from BITS-Pilani Hyderabad and the National Institute of Immunology (NII, Delhi).

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How would you explain your key results to the non-scientific community?

It is always the notion that to be simple is good rather than to being complex. However, the vast spectrum of living organisms ranges from single cellular bacterium to multicellular plants and animals. They all have their unique ways of survival and that growth. These different types of organisms can also interact with each other and hold a mutual relationship. For example, our gut flora consists of many bacteria, archaea, and fungi. In such cases, participants either exploit or share the nutrition and niche for better survival and growth. Most of the microbes in the human body are helpful in various biological functions such as digestion, educating our immune system, toxin neutralization, etc. While some of them are not. They can enter our body and cause severe harm, also known as infection. 

The human body has both natural and acquired ways to fight against these harmful microorganisms. But still, due to advanced evolutionary capabilities, sometimes they escape from it and successfully establish the infection. Interestingly, some can stay hidden or inactive for a long time and invade our system when our immune stamina is low. Mycobacterium tuberculosis (Mtb) is one of the smart bacteria which causes the commonly known disease TB (tuberculosis).

According to sources, a quarter of the world’s population (1.7 billion people) carries this microorganism (latently), and almost 159 people die every hour. Therefore, it is vital to understand the biology of the bacteria causing TB. Doctors are using various kinds of combinational drug regimens, and scientists are developing new sets of antibiotics and vaccines to combat it. 

One small step towards it, in the current research article, we have characterized few important and unique features of an essential gene of TB causing bacteria, named glmU. Just like our skin, microorganisms are also surrounded by a protective layer, known as “cell wall”. And this gene (glmU), present in most of the bacteria, including Mtb, is one of the key members to produce the cell wall. Our study deciphers that glmU in Mtb holds some distinct vital features that can be targeted while designing and developing new drugs against TB.

Schematic

our research provides a way to design new sets of inhibitors against these particular topographies of glmU, which can then indirectly affect many more pathways (glmU interacting partners). 

What are the possible consequences of these findings for your research area?

Although humans and bacteria are genetically diverse, the fundamental biochemical processes hold great levels of similarities. Therefore, it is difficult to select a biological molecule or process that can unambiguously affect the survival of an infection-causing bacteria (not the beneficial bacteria). glmU is present in many bacteria, but with the help of molecular biology and genetic engineering, our research shows that this gene (glmU) has distinct structural features and interactions with other important proteins, exclusive to Mtb glmU. It’s like one bullet, multiple targets. Thus, our research provides a way to design new sets of inhibitors against these particular topographies of glmU, which can then indirectly affect many more pathways (glmU interacting partners). 

What was the exciting moment (eureka moment) during your research?

We believe that every result, positive or negative, is a eureka moment for a researcher because it helps us strengthen or modify our hypothesis. Literature is full of many such studies talking about numerous characteristic characters of GlmU from various microorganisms. As GlmU is a very conserved protein and we were expecting that complementation of this gene in a glmU (gene) knockout strain of Mtb, would help Mtb survive. But we were wrong. We tried various closely related genes, and none of them rescued the bacteria, even GlmU from Mycobacterium smegmatis, which is the same family strain (with significant similarities). It was our awe moment and motivated us to dive deep into it. 

What do you hope to do next?

We as a researcher always hope to better the things we are already doing and continue working towards that. We have explored various dimensions of GlmU such as biology, role in infection, and crystal structure. GlmU synthesizes the fundamental building blocks of the bacterial cell wall, and with our in-depth understanding, we would like to explore other unknown biological and biochemical functions of GlmU and harness them for the development of better inhibitors against TB. 

Where do you seek scientific inspiration?

MA: I think that scientific inspiration comes in different forms to a scientist or a researcher. Primarily, its self-interest when you entered into the field. Since now you are exposed to the real world of research it can come from your mentors, colleagues, and most importantly from ongoing research into the field. That brings the importance of scientific meetings and conferences into the picture.

VS: My scientific inspiration comes from nature, observations, and questions. Every time I see any phenomenon or problem, my mind seeks the reason or solutions for it, and that drives me to read literature, discuss with mentors and colleagues and finally design experiments to test it. The quest for the unknown clicks in the brain and fuels my imagination to connect the dots to make a better picture. 

How do you intend to help Indian science improve?

Indian science has a huge potential and provides us with several opportunities. We intend to provide a very enthusiastic and learning environment in our research group and never let down anyone’s scientific temperament. We also believe in collaborative learning; therefore, we try to connect with new budding research minds and provide the necessary training in our laboratories. 

Reference

Meetu Agarwal, Vijay Soni, Suresh Kumar, Biplab Singha, Vinay Kumar Nandicoori; Unique C-terminal extension and interactome of Mycobacterium tuberculosis GlmU impacts its in vivo function and the survival of the pathogen. Biochem J 2021; BCJ20210170. doi: https://doi.org/10.1042/BCJ20210170

Edited by: Nivedita Kamath

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