The rise in antimicrobial-resistant “superbugs” urges us to expand the repertoire of antimicrobial strategies. Of particular interest are antibiotics that target bacterial membranes, since resistance to these antibiotics is hard to develop without compromising bacterial viability overall. Bacteriocins are promising candidates: e.g. nisin is already widely used as a food preservative that targets Gram-positive bacteria, but is not effective against Gram-negative bacteria, and e.g. epidermicin shows wide tuneability in its modes of membrane disruption. However, mechanisms of action on real bacterial membranes remain poorly understood, and substantial bioengineering remains necessary to reach the specificity and broad-range effectiveness required for next-generation antibiotics.
Over the past years, there has been extensive progress on the validation of various antimicrobial peptides and their modes of action on model membranes, often combining techniques such as nuclear magnetic resonance, molecular dynamics simulations, circular/linear dichroism, and atomic force microscopy (AFM). However, it remains technically challenging to acquire insights on their behaviour on real bacterial membranes. AFM now offers nanoscale-resolution visualisation of bacteria under antimicrobial attack, but it lacks chemical resolution and it struggles to detect dynamic binding and diffusion of biomolecules at membranes.
In this project, we aim to enhance such nanoscale visualisation approaches with single-molecule fluorescence microscopy. Single-molecule fluorescence microscopy readily offers millisecond temporal resolution of specifically labelled molecules. It thereby complements AFM, providing chemically specific information with enhanced scope for detecting biomolecular dynamics at membranes, and thereby also providing further input for bioengineering approaches to improve antimicrobial functionality.
For this project, we have direct technical support from our industrial partner ONI Ltd. A 3-month student placement is foreseen at ONI to further enhance this collaboration and to at the same time to provide the student with valuable industrial experience.
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