PhD in Pharmaceutical Sciences in kings college london

Project title

Molecular mechanisms of LPS-interacting antimicrobial peptides

Lipopolysaccharides (LPS) of Gram negative bacteria are major structural components of the cell envelope and the sepsis-inducing endotoxins of human pathogens. Sepsis has long been the most common cause of death in hospital intensive care units, a situation exacerbated by the increasing spread of bacterial antibiotic resistance. Even the use of effective antibiotics can lead to an increased risk of sepsis, since disruption of bacterial cells leads to the release of pro-inflammatory micellar LPS aggregates.

The ability to neutralise LPS toxicity is thus a desired requirement for future antimicrobial therapeutics. The development of such drugs will necessarily require a thorough characterisation of their molecular interactions with LPS and of the resulting aggregates formed.

In this project, the molecular mechanisms of a range of cationic antimicrobial peptides (CAPs) which are known to interact with LPS, will be examined using both solid-state NMR (at KCL) and neutron scattering techniques (at RAL). Whilst CAP interaction with LPS-free models of the bacterial membranes has been well characterised using a number of biophysical techniques, their interaction with LPS is not well understood.

Although there is compelling evidence supporting the direct binding of CAPs to LPS from optical spectroscopy measurements which demonstrate changes induced in peptide secondary structure as a result of such interactions, little is known about the resulting aggregate phases formed.

This project aims to achieve detailed characterisation of the interaction between LPS and endotoxin-neutralising CAPs, together with an elucidation of the solution structures of the aggregates formed, to validate the so-called “conformational concept of endotoxicity”.

To find out more, read application details.

Source: Kings College London
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