Coventry University Featured PhD Programmes
Peter MacCallum Cancer Centre Featured PhD Programmes
University College London Featured PhD Programmes

Uncovering the killing-mechanism of bactericidal antibiotics


Biosciences Institute

Dr H Strahl von Schulten , Dr GJ Sharples , Dr K Waldron Friday, January 22, 2021 Competition Funded PhD Project (Students Worldwide)
Newcastle United Kingdom Microbiology

About the Project

The majority of our clinically most successful antibiotics target surprisingly few cellular processes. The prominent first-line antibiotic-classes penicillins and cephalosporins, but also by the last resort antibiotics Vancomycin and Daptomycin used to treat life-threatening multidrug resistant infections, target the bacterial cell wall synthesis machinery. Aminoglycosides, macrolides and tetracyclines, in turn, target bacterial ribosomes and inhibit the protein translation process. While cell wall-targeting antibiotics are bactericidal, most ribosome-targeting antibiotics are bacteriostatic and, thus, inhibit bacterial growth without killing them. However, aminoglycosides form a striking exception from this trend and are strongly bactericidal through a mechanism that, despite extensive studies, is still not fully understood.  

Recently, we made a surprisingly discovery that cell wall-targeting antibiotics and aminoglycosides share a previously unrecognised antibacterial mode of action that contributes to their ability to induce rapid bacterial killing. Studying this newly identified cellular process will provide exciting insights into the core mechanisms that allow antibiotics to kill their target bacteria. This is important in order to understand how existing and widely used antibiotic classes work, but also to decipher why they share a comparatively low rate of antibiotic resistance (AMR) development. Hence, studying these processes will allow us to guide the development of the next generation of new antibiotics towards ones with intrinsically lower risk of resistance development.

In this collaborative project between the groups of Henrik Strahl and Kevin Waldron (Newcastle) and Gary Sharples (Durham), the newly discovered mode of action shared by cell wall and aminoglycoside antibiotics will be analysed using the Gram-positive model organism Bacillus subtilis and the model pathogen Staphylococcus aureus. The research programme makes extensive use of advanced microscopy techniques such as microfluidic devises, super resolution microscopy and high-speed imaging. The student will, thus, enjoy an exceptionally broad training in state-of-the-art methods in molecular and cellular microbiology, and in antibiotic research.

Informal enquiries may be made to

Twitter: @HenrikStrahl

HOW TO APPLY 

Applications should be made by emailing with a CV and a covering letter, including whatever additional information you feel is pertinent to your application; you may wish to indicate, for example, why you are particularly interested in the selected project/s and at the selected University. Applications not meeting these criteria will be rejected. We will also require electronic copies of your degree certificates and transcripts.

In addition to the CV and covering letter, please email a completed copy of the Newcastle-Liverpool-Durham (NLD) BBSRC DTP Studentship Application Details Form (Word document) to , noting the additional details that are required for your application which are listed in this form. A blank copy of this form can be found at: https://www.nld-dtp.org.uk/how-apply.


Funding Notes

Studentships are funded by the Biotechnology and Biological Sciences Research Council (BBSRC) for 4 years. Funding will cover tuition fees at the UK rate only, a Research Training and Support Grant (RTSG) and stipend. We aim to support the most outstanding applicants from outside the UK and are able to offer a limited number of bursaries that will enable full studentships to be awarded to international applicants. These full studentships will only be awarded to exceptional quality candidates, due to the competitive nature of this scheme.

References

1: Antimicrobial peptide cWFW kills by combining lipid phase separation with autolysis. Scientific Reports, 2017, 7:44332
2: Daptomycin inhibits cell envelope synthesis by interfering with fluid membrane microdomains. PNAS, 2016, 113:7077-7086
3: Analysis of antimicrobial-triggered membrane depolarisation using voltage sensitive dyes. Frontiers in Cell and Developmental Biology, 2016, 4:29
4: The actin homologue MreB organizes the bacterial cell membrane. Nature Communications, 2014, 5:3442
5: Membrane potential is important for bacterial cell division. PNAS, 2010, 107:12281-12286
6: Mycobacterium tuberculosis RuvX is a Holliday junction resolvase formed by dimerization of the monomeric YqgF nuclease domain. Molecular Microbiology, 2015, 100:656-674
7: Mutants of phage bIL67 RuvC with enhanced Holliday junction binding selectivity and resolution symmetry. Molecular Microbiology, 2013, 89:1240-1258
8: A superoxide dismutase capable of using iron or manganese promotes the resistance of Staphylococcus aureus to calprotectin and nutritional immunity. PLoS Pathog. 13, e1006125 (2017).
9: An evolutionary path to altered cofactor specificity in a metalloenzyme. Nat Comms 11: 2738 (2020)
10: A four-helix bundle stores copper for methane oxidation. Nature 525: 140-3 (2015).
Search Suggestions

Search Suggestions

Based on your current searches we recommend the following search filters.



FindAPhD. Copyright 2005-2021
All rights reserved.