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Molecular design and biophysical analysis of a new class of membrane-rupturing peptide antibiotics


Project Description

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 [1]. 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 [2]. 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 [1]. 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 [3].

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 () Informal enquiries may also be made with Prof Tabor or Prof Howorka (). 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 ().

More about research can be found at:
https://www.ucl.ac.uk/chemistry/people/professor-alethea-b-tabor
http://www.howorkalab.com

References:
[1] J. Medeiros-Silva et al., Nature Commun. 2018, 9, e3963
[2] S. A. Mitchell et al., Bioorg. Med. Chem. 2018, 26, 5691
[3] J. R. Burns et al., Nature Nanotechnol. 2016, 11, 152.

Funding Notes

Due to funding restrictions, this studentship is only open to applicants from the UK and EU who have been resident in the UK for at least 3 years preceding their start on the programme.

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