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The increasing emergence of antibiotic-resistant bacterial strains, such as methicillin-resistant Staphylococci aeurus (MRSA) is driving the development of new technologies to investigate antibiotics. This thesis describes the use of BioMEMS cantilever technology for the label-free detection of glycopeptide antibiotics in solution, at concentrations as low as ~ 1 nM. Multiple cantilever arrays were used to detect the antibiotics vancomycin, ristomycin, chloroeremomycin and oritavancin, which are often considered as the ‘last line of resistance’ to bacterial infections. Cantilevers wee coated with thiolated mucopeptide analogues found in antibiotic-sensitive bacteria and mutated peptides found in resistant strains. Drug-mucopeptide binding was found to generate a compressive surface stress and could discriminate the deletion of a single hydrogen bond associated with resistant peptides. Measured binding constant were in close agreement with reported data. Building on these findings, a new model is proposed to describe the propagation of surface stress on cantilevers and considers two factors – a chemical binding factor describing local drug-target interactions and a factor describing the mechanical connectivity –percolation – of the system. These findings and underlying concepts will simplify the design of new coating and devices to significantly enhance drug detection sensitivity. The second part of this thesis describes two novel approaches to optimise microcantilever technology. The first approach investigates the role of the gold adhesion layer by comparing silane self-assembled monolayers with conventional chromium/titanium layers. The second approach describes finite element simulations of a novel silicon-metal hybrid strain gauge with gauge factors of up to 800 that could be used as an alternative to optical cantilever bending detection. Prototype strain gauges were fabricated and tested, where the measurements were shown to agree remarkably well with the simulations.

Sulfonamides are important therapeutic agents and have a diverse array of biological functions in biology and medicine. Their means of synthesis has often involved the use of unstable sulfonyl chloride species; however, recent research has established pentafluorophenyl (PFP) sulfonate esters as a useful stable alternative to such species. This thesis describes the use of PFP vinyl sulfonate in a [3+2] cycloaddition with a variety of N-methyl-nitrones, providing access to the corresponding 4C-substituted isoxazolidine in a regio- and diastereoselective manner. Aminolysis of the resultant PFP sulfonate ester then provides functionalised sulfonamides of potential biological utility. In addition, the [3+2] cycloaddition reaction of several vinyl sulfonamides with N-methyl-nitrones is reported. Regiospecificity of the reaction is poor, nevertheless a diverse collection of heterocyclic sulfonamide structures have been isolated. Further attempts to further diversify the isoxazolidine products generated from [3+2] cycloaddition chemistry were carried out. The synthesis of isoxazoles from isoxazolidines was explored, and in the process a novel tertiary amine catalysed 'cycloaddition' has been discovered. The resulting isoxazolidine products were assessed as potential biological probes against various enzymes/diseases, and as a result a collection of products were submitted for biological evaluation against the enzymes dimethylarginine dimethylamino hydrolase (DDAH) and arginine deiminase (ADI). Several compounds displayed \muM inhibition against DDAH and ADI; and in addition, these currently represent the first known inhibitors of ADI. During the course of our investigation, it was also revealed that a small assortment of our heterocyclic sulfonamides possess good anti-HIV activity at concentrations of 75-100\muM. Attempts to isolate the cellular target, through modifications to our drug candidates for the purpose of affinity chromatography have also been explored.

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