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Sam Connelly is from London and joined Oxford Brookes as a research student in September 2016. His thesis title is ‘Understanding the Genome-wide response of Streptomyces coelicolor to the Glycopeptide Antibiotic Teicoplanin’.
I originally heard about Oxford Brookes through FindaPhD.com. My supervisor Dr Hee-Jeon Hong was advertising a PhD that really caught my eye. After applying for the PhD, I started to do some research on the University and was really impressed to see a university that cared about not only their students, but the global community as well.
Shortly after applying, I was invited for an interview. My first impressions of the University were really positive; the staff and faculty were really friendly and I felt like there was a real sense of community within the department. Even before receiving my offer, I felt that the University would be a good place to continue my academic career.
My supervisor focuses on antimicrobial resistance, and this has been an area that I have had an interest in since my bachelor’s degree. The project offered me the chance to carry out interdisciplinary research by navigating the fields of molecular microbiology and bioinformatics, providing me with more in depth skills in my previous discipline, whilst developing a new skill set in a field I had little prior knowledge of before.
Before starting this PhD, I was a research assistant working in a molecular microbiology laboratory in Leicester. I was designing marketable diagnostic tests for clinical pathogens that can be tricky to diagnose in hospitals.
I was also running my own science communication blog 23pairsofchromosomes.com with a team of students around the world. Together we would write our own interest articles, aimed at a wider audience. We wrote about a wide variety of topics from limb regeneration in salamanders, to antimicrobial proteins. It was a lot of fun getting involved in science in a completely different environment, and we received a lot of positive feedback from the online community.
The summer before starting my PhD, I was also employed as a private tutor teaching both biology and chemistry. I really enjoyed helping students improve in their studies. I found it really interesting to see that even students who had not been doing well previously, could be encouraged to perform better if given the right guidance. I also realised how important teaching can be within science. It’s important as an academic to pass on your knowledge to others, and teaching is a great way to do this.
I was thrown in at the deep end in the first few months of my project. I had to learn how to run command lines in UNIX and programme in R to carry out my statistical analysis, yet I didn’t have much experience in either. Luckily, I had a great support network around me to give me a gentle nudge in the right direction, and after about six months of doing the PhD, my confidence started to grow and my project really started to take off. The academic world is a little bit of a rollercoaster at times, and some weeks can be more challenging than others, but now I feel far more confident with what I’m doing so when I approach new tasks, they aren’t so intimidating.
Bacteria are constantly faced with a whole plethora of stressful challenges and their stress response can determine whether they live or die. In particular, stress caused by antibiotics has become gravely important in medical settings as antibiotic stress has given rise to ‘superbugs’. These are bacteria that have developed coping mechanisms to deal with such stress, consequently dwindling our armamentarium of antibiotics whilst threatening to hurl us into a post-antibiotic era. The problem has been exacerbated by the decline in new drugs reaching the market, commanding stricter measures on the most important antibiotics in an effort to slow the development of resistance against them.
Of particular importance are the Actinomycete-derived glycopeptide antibiotics. There are several commonly used glycopeptides employed in clinical medicine including the related drugs vancomycin and teicoplanin. Both are last resort drugs and are particularly effective in treating a number of severe hospital acquired infections caused by Gram-positive bacteria including methicillin-resistant Staphylococcus aureus (MRSA), which caused 80,000 severe infections and 11,000 deaths due to bacteraemia during 2013 in the United States alone.
Glycopeptides act on bacteria by targeting the cell surface, interfering with its maturation. Consequently the integrity of the cell is compromised making it more susceptible to rupture. The first resistant clinical isolates were identified in the 1980s, which employed strategies for altering their cell surface, reducing the efficacy of glycopeptides and maintaining cell wall integrity.
Although we have a good understanding of the resistance mechanisms behind vancomycin, we have a poor understanding of those specifically for teicoplanin. Work carried out on a harmless model actinomycete, Streptomyces coelicolor, has been helpful in understanding these drugs because even though it lacks the capacity to produce glycopeptide antibiotics, it does possess the intrinsic resistance to vancomycin similar to those seen in pathogenic bacteria. Recent work has shown that one of the genes found in S. coelicolor is able to decrease teicoplanin sensitivity but this effect does not cross over to vancomycin. This indicates that there are possible separate classes of genes involved in resistance to these two very closely related drugs.
There could be more resistance genes hiding within the genome of S. coelicolor that are also able to confer some resistance to teicoplanin and other glycopeptides. Finding these will help to improve our understanding for how this drug in particular works. To do this, we are employing the latest RNA sequencing (RNA-seq) technologies to understand the expression of all the genes within S.coelicolor after exposure to teicoplanin. Through identifying which genes change the most, we may be able to glean an insight into which genes are the most useful when responding to the damage caused by this antibiotic and develop strategies to prolong its clinical use.
The best thing about being a research student is being able to focus on an area that you are interested in. If you have a real passion for what you do, it makes all the struggles of the PhD worth it.
That being said, there will be new challenges with any project. Whenever I start anything new in the lab or on the computer, it’s always a challenge at first to get to grips with the new skills I need for different tasks. The best strategy for overcoming this has been to build confidence in my own abilities, and being a little easier on myself when things don’t go to plan. PhDs are about persistence; if you stick with something long enough, then things will work out.
Most of the training I’ve received at Brookes has been really helpful with my career development. Not all of it has been relevant to me, so it’s important that you choose the courses that will be helpful. But Brookes offer enough training to make sure that the PhD students are well prepared throughout their course.
Currently I’m sitting on the fence about my future career. I haven’t quite settled on where I want to end up. I do want to stay in research for a while after my PhD if I can find a post-doc either here or elsewhere, but I may find after a few more years in academia, it isn’t for me. The great thing about doing a PhD is that you pick up so many transferable skills; you really have a lot of options when you finish, but it’s all up to you where you end up.