About the Project
Antimicrobial resistance (AMR) has become a global crisis threatening our health care system and causing huge economic loss. Among AMR bacteria, methicillin resistant S.aureus (MRSA) is one of the most common causes of operation wound infections, blood stream infections and nosocomial pneumonia. Currently MRSA strains are resistant to nearly all beta-lactam antibiotics, leaving few options for treatment of MRSA infections due to emerging MRSA strains with resistance to ‘last resort ‘antibiotics. There is thus urgent need to study the novel resistance mechanisms of MRSA and develop novel diagnostics and antibiotics to combat MRSA infection.
Like most gram positive bacteria, S. aureus is densely decorated with wall teichoic acids (WTAs), which play critical roles in cell division, biofilm formation, and interactions with host cells and bacteriophages.1-3 Wall teichoic acids are phosphate-rich anionic glycopolymers, composed of repetitive ribitotolphosphate (RboP) connected via 1,5 phosphodiester bonds, and substituted with D-Alanyl at C2-OH and/or GlcNAcylation at C4-OH via either α- or β-glycosidic bonds. The main chains of WTAs are covalently linked to the cell wall peptidoglycans via a p-GlcNAc-ManNAc disaccharides and bis-glycerolphosphate (GroP).
Recently the glycosylation pathways has been elucidated for WTA in S aureus.1 Whereas WTA GlcNAc residues are required for staphylococcal adhesion and activation of complement cascade,1 only WTA β-GlcNAc residues are specifically required for β-lactam resistance.2 A few WTA interaction proteins have been identified and characterized,3 however, lack of pure WTA oligomers with defined substitutions/length greatly hinders investigation of WTA interactions.
Of note, Fondaparinux, a heparin sulphate (HS) pentasaccharide, has been co-crystallized with a WTA GlcNAc transferase, suggesting WTAs share similar physicochemical properties with HS. Based on our expertise in both HS chemistry4-6 and WTA biology,1-3 we aim to develop a new approach to generate diverse, pure, site-programmable WTA fragments, which provide powerful tools to probe the biology of WTA interactions and thereby underpin the potential development of approaches to novel diagnostics and antibiotics.
Qualifications
Applicants should have or expect to obtain a good 1st or II(i) honours degree (or an equivalent degree) in a relevant subject.
Gardiner group - http://www.gardinergroup.org.uk
Xia Group-http://www.manchester.ac.uk/research/guoqing.xia/
Contact for further Information
For more details contact Dr J Gardiner ([Email Address Removed])
Funding Notes
Applications are invited from self-funded students or students who have funding in place and require an offer or to secure funding e.g. CONACyT require an offer. For UK/EU tuition fees are £8500 and International are £24,500 for 2018/19 academic year.
References
1. Winstel V, Xia G*, Peschel A. Int. J. Med. Microbiol, (2014), 304(3-4):215-221
2. Brown S, Xia G*, Luhachack LG, Campbella J, Meredith T, Chen C, Winstel V, Gekeler C,Irazoqui JE, Peschel A, Walker S*. Proc. Natl. Acad. Sci. USA (2012), 109: 18909-14. ( *Joint corresponding author)
3. Li X , Koc C, Kuener P, Stierhof Y, Enright MC, Penades JR, Wolz C, Stehle T, Cambillau C,Peschel A, Xia G. Sci Rep (2016), 6, [26455].
4. Gardiner JM et al. J. Org. Chem. (2015), 80, 3777-3789.
5. Jayson GC, Gardiner JM et al. Chemical Science (2013), 4: 3218-3222.
6. Jayson GC, Gardiner JM et al Nature Commun. (2013), DOI: 10.1038/ncomms3016.
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