The antibiotic fusidic acid (FA) blocks bacterial protein synthesis by interacting with Elongation-factor G (EF-G). Resistance to FA is caused by FusB, which interacts with EF-G, altering its motion. Research by the second supervisor has shown that FA resistance can be overcome by preventing the EF-G/FusB interaction, identifying the key binding area on EF-G.
Using a fluorine-containing fragment library developed at Leeds, the supervisors have identified fragments binding to EF-G using Nuclear Magnetic Resonance (NMR). This project will further investigate the binding mode of these fragments, prioritizing those interacting with EF-G's FusB binding region, and elaborate them into small molecules to prevent FA resistance.
Antibiotic adjuvants such as Avibactam are a validated approach to block resistance mechanisms and enhance efficacy of existing antibiotics. A potential EF-G/FusB inhibitor used in combination with FA would represent a first-in-class antibiotic.
The World Health Organization declared antimicrobial resistance a great threat to health. New treatments to circumvent resistance mechanisms would help alleviate this. This project builds on current work which has developed a fragment screening library and the workflow necessary to identify fragments binding to proteins of interest.
Objective 1: Validated fragment binders will be analyzed using protein-observed 1H-15N amide and 1H-13C methyl NMR to determine where they bind on EF-G. Spectra are well established, and spectrum assignments available.
Objective 2: The de novo molecular design tool SPROUT will be used to elaborate fragments binding at the EF-G/FusB interface (based on information from objective 1) into molecules which will be synthesized for evaluation in objective 3.
Objective 3: Synthesized ligands will be screened for activity using a fluorescence assay, monitoring the build-up of stalled ribosome complexes in vitro, allowing determination of whether the molecule can influence FusB-mediated FA resistance. Ligands showing inhibition will be tested on S. aureus harbouring FusB to determine change in efficacy.
We are committed to fostering a positive research culture. We actively promote equity, diversity and inclusion, including by facilitating flexible working, empowering and valuing team members and their contributions, embracing diversity and encouraging team members to participate in development opportunities. Institutionally, and at a local level we are committed to delivering on the aims of the researcher development concordat. We collaborate widely with other groups and the student will be part of the Astbury Centre, which include like-minded PGRs and staff members. In addition to weekly group meetings and journal clubs, the Astbury Centre hosts annual research retreats linked to a social event to encourage team working and support networking. The Faculty of Biological Sciences (where the lead supervisor and second supervisor is a PI) holds an Athena Swan Silver Award.
Applicants to research degree programmes should normally have at least a first class or an upper second class British Bachelors Honours degree (or international equivalent) in an appropriate discipline.
Applicants whose first language is not English must provide evidence that their English language is sufficient to meet the specific demands of their study. The minimum English language entry requirement for postgraduate research study in the Faculty of Biological Sciences is an IELTS of 6.0 overall with at least 5.5 in each component (reading, writing, listening and speaking) or equivalent. The test must be dated within two years of the start date of the course in order to be valid.
To apply for this project applicants should complete an online application form and attach the following documentation to support their application.
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