New antimicrobial agents are urgently needed in order to combat the threat of antibiotic resistance. Nisin, a complex polycyclic peptide, is a promising lead. It binds with high selectively to bacterial lipid II to rupture the cell membrane via nisin-lipid II pores . However, to exploit this remarkable activity for developing new simple antimicrobial agents, a thorough understanding of nisin’s structure-function relationship is necessary. The key questions are: how does nisin’s structure influence the mechanism and kinetics of pore formation; and what is the detailed architecture of the pore?
In this project, the student will address these important challenges by synthesising simplified nisin-like peptides and studying their bactericidal activity and biophysical properties. The starting point are recently created simplified nisin-like peptides in which the lipid II-binding motif of nisin (residues 1-12) is conjugated to linear pore-forming peptides . These hybrid peptides have good activity against Gram-positive bacteria. Input for the design of simple peptides also comes from a recent solid-state NMR study of the nisin-lipid II pore which suggests that structures such as one of nisin’s rings (C) may be critical for pore formation, whilst the C-terminal sequence may be unstructured . Our aim is to create a platform of nisin variants with linear, circular or shortened peptides to identify those structural components essential for pore forming and bactericidal activity. To study lipid II-binding and pore-forming, fluorescence binding assays and nanopore recordings will be used .
The requirement for this studentship is a first class or upper second-class honours degree (MSci, MChem) or equivalent. Applications, including a cover letter and full and up-to-date CV, together with the names, addresses and email addresses of two academic referees should be sent as soon as possible to Prof Tabor ([email protected]) Informal enquiries may also be made with Prof Tabor or Prof Howorka ([email protected]). Suitable candidates will be required to complete an electronic application form at http://www.ucl.ac.uk/prospective-students/graduate/apply. Any admissions queries should be directed to Dr Jadranka Butorac ([email protected]).