Vögtli, M.; (2011) Nanomechanical detection of drug-target interactions using cantilever sensors. Doctoral thesis , UCL (University College London).

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Abstract

The alarming growth of antibiotic-resistant superbugs including methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococci (VRE) is driving the development of new technologies to investigate antibiotics and their modes of action. Novel cantilever array sensors offer a tool to probe the nanomechanics of biomolecular reactions and have recently attracted much attention as a ’label-free’ biosensor as they require no fluorescent or radioactive tags and so biomolecules can be rapidly assayed in a single step reaction. Thereby, cantilever-based sensors are unique in the sense that they can measure an in-plane nanomechanical surface stress which is not purely mass dependent. This thesis reports the label-free detection of drug-target interactions on microfabricated cantilever arrays focusing on the vancomycin family of antibiotics. Vancomycin has remained at the forefront of the battle against MRSA and works by targeting the outer cell wall of bacteria, nevertheless little is known about how the drug binding interactions lead to a large scale mechanical weakening of the cell and consequently cell death by lysis. In this thesis three key developments are reported: (i) the development of experimental protocols and cantilever instrumentation to enable robust, specific and sensitive drug-target measurements in buffer and blood serum, (ii) a detailed investigation of the nanomechanical transduction mechanism which identified a critical density of surface ligands for the generation of stress and may have important implications on the mechanical mode of action of glycopeptides on the bacteria cell wall, and (iii) the first use of this technology to analyse drug targets on tethered lipid layers that closely mimic the surface of bacteria. These findings and underlying concepts represent major milestones for this promising technology and may also contribute to our understanding of how antibiotics actually kill bacteria and thereby advance the search for a new generation of drugs in the battle against superbug resistance.

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