Postgraduate Pioneers 2017 #1

 

 

Today, we can survive an organ transplant but then die because of a bacterial infection. The rise of antimicrobial resistance (AMR) and ‘superbugs’, along with the lack of antibiotic development in the last decades, is a major concern for global healthcare. Whilst there are several mechanisms responsible for AMR, our research group is examining multidrug efflux pumps or transporters that expel drugs rendering bacteria resistant to a broad range of antibiotics. 

 

While we know some things about the architecture of bacteria, we don’t fully understand how they conduct transportation of antibiotics. If we could understand their operating system, we could develop compounds, which might help switching off the system and stop them from rejecting antibiotics. In particular, my project is looking into a very interesting E.coli ATP-binding cassette (ABC) transporter MsbA. We are working towards characterising how this protein uses energy to operate dynamic changes in its structure to facilitate drug transport. 

 

 

During my master's degree, I worked with AstraZeneca and my neighbouring lab was working on transporters in drug development. Their work caught my attention. I also visited India that summer and my hometown, Gwalior, in Madhya Pradesh, was suffering a severe outbreak of tuberculosis and typhoid. These experiences exposed me to the seriousness of antibiotic resistance. Transporters play a huge role in this and after reading up on the topic, I looked for a relevant PhD project and was delighted to be accepted into Dr Hendrik W. van Veen's lab to work on various transporters, both in humans and bacteria.

 

 

I am based in the Department of Pharmacology, which is in the city center – it’s a great location. I work in a team of ten and my average day in the lab is spent working on culturing liters of bacterial cells to extract MsbA and reconstitute it in artificial lipid membranes. I then test MsbA activity under different energy conditions and drugs, or test different inhibitors. 

 

 

That has to be when we first noticed that the ATP dependent transporter MsbA could also work without ATP. ATP is an energy currency of cells and ABC transporters, such as MsbA, utilize it as their main source of power for drug transport. But we showed that MsbA is also dependent on another form of energy source, an electrochemical gradient. In fact, MsbA cannot function without the involvement of both of these power sources. That brought a paradigm shift in our understanding of translocation by MsbA, which may lead us to new ways to tackle bacteria.

 

 

Apart from being a multidrug transporter, MsbA is an essential membrane protein that transports phospholipids in E.coli to form its cell membrane; so inhibiting this pump is clinically important to develop or establish foundations for a new class of antibiotics against E.coli. We can only design inhibitors if we know the fundamental basis of their transport mechanism and I hope my PhD research will provide some insight into this.  We believe that our findings will be of great interest to the wider scientific community. 

 

 

My supervisor, Dr. Hendrik W. van Veen has played a crucial role in developing my enthusiasm for scientific research. And Cambridge has provided a tight-knit, supportive and stimulating intellectual environment which has shaped my career and understanding of academia in really important ways. Other than benefiting from the world-class research facilities in my lab and department, I’ve been able to immerse myself in Cambridge’s rich culture and exciting critical atmosphere. The collegiate system also ensures a thriving social life and this paved the way for me to develop interests in various other disciplines over formal dinners and drinks in our college bars.