Dr G Florence, Dr U Schwarz-Linek
No more applications being accepted
Funded PhD Project (European/UK Students Only)
About the Project
Introduction: The threat of antimicrobial resistance (AMR) has been recognised globally as one of the most significant problem facing mankind in the 21st century. New approaches for the treatment of bacterial infections are of paramount importance to societies in the UK and elsewhere. Conventional efforts to combat AMR rely on the discovery of new antibiotic drugs. These however will inevitably induce resistance, resulting in a never-ending arms race with bacteria. An alternative approach to treating bacterial infections does not rely on antibiotics (i.e. agents that kill bacteria) but targets bacterial virulence factors, proteins required for establishing colonisation of and persistence in the host, such as bacterial surface proteins.
Novel antimicrobial agents capable of preventing adhesion to host tissues are promising alternatives to antibiotics, in particular since they do not directly affect bacterial viability, and therefore would not give rise to resistance. Any mutations evolving in response to anti-virulence drugs would also impair the ability of bacteria to interact with their host (Krachler AM, Orth K 2013 Virulence 4:284). Anti-adhesion drugs have proved elusive since the extensive, multivalent interactions at bacteria:host interfaces are difficult to inhibit using small molecules. In contrast, we identified a new class of Gram-positive surface proteins for which such drugs could prove effective. These contain internal thioester bonds in adhesin domains (TEDs) that mediate specific interactions with host tissue through formation of covalent bonds (Walden M et al. 2015 eLife 4:e0663). We have developed prototypes of bifunctional irreversible inhibitors of bacterial thioester bonds that impair binding of TEDs to model host cells. Such inhibitors should be active in very low concentrations due to the irreversible, covalent mode of action.
Project Plan
This project aims to develop a range of irreversible TED inhibitors that can serve as antimicrobial agents but also as tools for studying fundamental aspects of bacterial pathogenesis. The interactions of inhibitors with bacterial surface proteins will be studied using recombinant proteins and bacteria such as Clostridium difficile and vancomycin-resistant enterococci (VRE). The project combines synthetic organic chemistry, medicinal chemistry, protein biochemistry, structural biology and microbiology. The specific aims are:
1) development of TED-specific bi- and tri-functional inhibitors
2) design of nanogold-labelled TED-specific probes for electron microscopy
3) structural characterisation of novel TEDs from clinically relevant Gram-positive bacteria
4) structure-based design of highly specific TED inhibitors
5) validation of TEDs as drug targets in an animal model of C. difficile infection (existing collaboration with Dr Gillian Douce, Glasgow and Dr Robert Fagan, Sheffield)
Training
The PhD student will join the research groups of both supervisors, both located in the Biomedical Sciences Research Complex. This interdisciplinary proposal brings together expertise in molecular biology and synthetic chemistry to provide an innovative approach to the understanding the TED adhesion system and its potential as a new target to tackle AMR. A programme of multidisciplinary research at the interface of chemistry and biology will provide intellectual challenge and high quality training with unique opportunities for creativity and inventiveness. The student will become highly trained in the arts of microbiology, enzyme assays, rational drug design and synthetic medicinal chemistry.
Funding Notes
This is a University of St Andrews St Leonards College Interdisciplinary PhD Scholarship Award in the Biomedical Science Research Centre in the Schools of Chemistry and Biology. The PhD scholarship will be jointly supervised by Dr Uli Schwarz-Linek and Dr Gordon Florence as part of a multidisciplinary collaborative project. Applications will be considered from UK and EU applicants.
Please see: http://www.st-andrews.ac.uk/chemistry/prospective/pg/ for the application procedure or e-mail [Email Address Removed] for more information regarding PhD opportunities at St Andrews.
References
Krachler AM, Orth K 2013 Virulence 4:284
Walden M et al. 2015 eLife 4:e0663