The bacterial cell envelope is the target for some of our most successful antibiotics including penicillins and cephalosporins, and also for last-resort antibiotics such as vancomycin and daptomycin used to treat life-threatening multidrug-resistant bacterial infections. The core mechanism through which envelope-targeting agents kill bacteria is by activation of the bacterium’s own cell wall-degrading enzymes; a process ultimately resulting in bacterial death by cell lysis. However, some individual bacterial cells can escape the induced lysis thereby giving rise to antibiotic resistance and recurrent infections. Despite the central importance of induced bacteriolysis for antibiotic function, our understanding of it is surprisingly superficial. While most proteins and components involved in cell wall synthesis and degradation are well characterised, how antibiotics hijack these native cellular processes in order to induce cell lysis is largely unknown.
In this PhD project, we will study the exact cellular steps leading into antibiotic-induced bacteriolysis focussing on the rod-shaped model bacteria Bacillus subtilis and Escherichia coli, and on the coccoid model pathogen Streptococcus pneumonia; the major causative agent for community-acquired pneumonia. We will use cutting-edge fluorescence microscopy techniques to follow the lysis process at a single cell level, with high spatial and temporal resolution. This core approach will be combined with the use of genetically modified bacterial strains deficient for known components of the cell envelope synthesis processes. This will provide us with an unprecedented insight in to the order of events associated with the bacteriolytic process including the proteins and pathways involved.
The emergence of multi-drug resistant bacterial pathogens is rapidly developing into a serious threat to global health. Consequently, antibiotic resistance and the development of new, resistance-breaking antibiotics is a top research priority identified by both the UK health authorities and the World Health Organization. By focussing on a surprisingly poorly understood, yet crucial aspect of antibiotic activity and studying how individual bacteria can escape lysis, this project will improve our understanding as to how many of the most successful antibiotics act. Ultimately, the results will guide the search and development of novel antibiotics with an intrinsically reduced risk of resistance development.
In this collaborative project between the Strahl (www.ncl.ac.uk/cbcb/staff/profile/hstrahl.html) and Fenton (www.sheffield.ac.uk/mbb/staff/andrewfenton/andrewfenton) groups, the PhD student will enjoy broad training in state-of-the-art techniques in molecular and cellular biology with strong focus on high-end fluorescence microscopy, and antibiotic research with emphasis on mode of action studies. The PhD programme will be carried out at the Newcastle University Centre for Bacterial Cell Biology (www.ncl.ac.uk/cbcb), a world-class microbiology research centre. Research placements with the collaboration partner at the Sheffield University Department of Molecular Biology and Biotechnology (www.sheffield.ac.uk/mbb) are also planned providing the student with hands-on experience in working with pathogenic bacteria. The combination of the research topic investigating the fundamental mechanisms underlying antibiotic function, the use of cutting-edge techniques and practical experience working with model pathogens will provide a strong basis for a future career in antibiotic research, in both academia or industry.
Follow us on Twitter: @henrikstrahl and @andrewkfenton
Benefits of being in the DiMeN DTP:
This project is part of the Discovery Medicine North Doctoral Training Partnership (DiMeN DTP), a diverse community of PhD students across the North of England researching the major health problems facing the world today. Our partner institutions (Universities of Leeds, Liverpool, Newcastle and Sheffield) are internationally recognised as centres of research excellence and can offer you access to state-of the-art facilities to deliver high impact research.
We are very proud of our student-centred ethos and committed to supporting you throughout your PhD. As part of the DTP, we offer bespoke training in key skills sought after in early career researchers, as well as opportunities to broaden your career horizons in a range of non-academic sectors.
Being funded by the MRC means you can access additional funding for research placements, international training opportunities or internships in science policy, science communication and beyond. See how our current DiMeN students have benefited from this funding here: http://www.dimen.org.uk/overview/student-profiles/flexible-supplement-awards
Further information on the programme can be found on our website: http://www.dimen.org.uk/
Flores-Kim J, Dobihal GS, Fenton A, Runder DZ & Bernhardt TG (2019) A switch in surface polymer biogenesis triggers growth-phase-dependent and antibiotic-induced bacteriolysis. eLife, 8.
Müller A, Wenzel M, Strahl H, Grein F, Saaki TNV, Kohl B, Siersma T, Bandow JE, Sahl H-G, Schneider T, Hamoen LW. Daptomycin inhibits cell envelope synthesis by interfering with fluid membrane microdomains. PNAS 2016, 113(45), E7077-E7086.
Strahl H, Bürmann F, Hamoen LW. The actin homologue MreB organizes the bacterial cell membrane. Nature Communications 2014, 5, 3442.