Synthesis of symmetrical ruthenium(II)-based inhibitors of bacterial type IIA topoisomerases
About the role
Synthesis of symmetrical ruthenium(II)-based inhibitors of bacterial type IIA topoisomerases
Key information
This sandwich placement will be based in the lab of Jeannine Hess.
Project summary
This project will focus on the chemical synthesis of symmetrical terpyridine ligands coordinated to a Ru(II) metal center. These complexes are rationally designed to target the bacterial enzymes DNA gyrase and topoisomerase IV (Ruthenium-based topoisomerase inhibitors, RuBTIs). The inhibitors are based on an organic scaffold, the Novel Bacterial Topoisomerase Inhibitors (NBTIs) originally discovered by GSK, which combines a DNA-intercalating “left-hand side” (LHS) motif with an enzyme-binding “right-hand side” (RHS) motif.[1] Previously, tris-heteroleptic Ru(II) complexes with these targeting groups were synthesised with potent activity in S. aureus, and a co-crystal structure of the complexes with S. aureus DNA gyrase was obtained, providing both the basis for further structural optimisation and confirming on-target activity.[2]
The student will synthesise a new generation of symmetrical RuBTIs and fully characterize them using spectroscopic and analytical techniques. The student also can test complexes against S. aureus DNA gyrase and Topo IV in biochemical gel-based assays and determine their in vitro bacterial activity via Minimum Inhibition Concentration (MIC) experiments (if desired).
Candidate background
The post holder should embody and demonstrate the Crick ethos and ways of working: bold, open and collegial. The candidate must be registered at a UK Higher Education Institution, studying in the UK and must have completed a minimum of two years’ undergraduate study in a relevant discipline, and on track to receive a final degree grade of 2:1 or 1. In addition, they should be able demonstrate the following experience and key competencies:
- This project would suit candidates with a chemistry background who are interested in organic/inorganic chemistry and drug discovery, and who are keen to work at the interface between synthetic chemistry and biology. Enthusiasm for molecular biology techniques would be a bonus, but is not essential.
- A foundation in organic or medicinal chemistry, with an interest in extending this into inorganic and bioinorganic systems
• Curiosity about how chemical synthesis can be applied to address problems in antimicrobial drug discovery
• Curiosity about how chemical synthesis can be applied to address problems in antimicrobial drug discovery - Good knowledge in relevant scientific area(s)
- Good written and spoken communication skills
- Ability to work independently and also capable of interacting within a group
References
1. Bax, B.D., Chan, P.F., Eggleston, D.S., Fosberry, A., Gentry, D.R., Gorrec, F., . . . Gwynn, M.N. (2010)
Type IIA topoisomerase inhibition by a new class of antibacterial agents.
Nature 466: 935–940. PubMed abstract
2. Ho, P.-Y., Rees, T.W., Phillips, M.A., Jin, E., Christodoulou, E., Purkiss, A.G., . . . Hess, J. (2026)
Preprint: Rationally designed ruthenium(II) complexes combat drug resistance in Staphylococcus aureus via type IIA topoisomerase inhibition.
Available at: ChemRxiv