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Despite the large arsenal of antibiotics available on the market, treatment of bacterial infections becomes more challenging in view of the fact that microbes develop resistance against existing drugs. There is an obvious need for novel drugs acting on both old and new targets in bacteria. In this thesis we have employed a whole cell bacterial assay for screening and identification of type III secretion system (T3SS) inhibitors in Yersinia pseudotuberculosis. The T3SS is a common virulence mechanism utilized by several clinically relevant Gram-negative bacteria including Salmonella, Shigella, Pseudomonas aeruginosa, Chlamydiae and Escherichia coli. Several components in the T3SS have proved to be conserved and hence data generated with Y. pseudotuberculosis as model might also be valid for other bacterial species. We have screened a 9,400 commercial compound library for T3S inhibitors in Y. pseudotuberculosis using a yopE reporter gene assay. The initial ~ 30 hits were followed up in a growth inhibition assay resulting in 26 interesting compounds that were examined in more detail. Three of the most interesting compounds, salicylanilides, 2-hydroxybenzylidene-hydrazides and 2-arylsulfonamino-benzanilides, were selected for continued investigations. The inhibitor classes show different profiles regarding the effects on T3SS in Yersinia and their use as research tools and identification of the target proteins using a chemical biology approach will increase our understanding of bacterial virulence. The 2-hydroxybenzylidene-hydrazides have been extensively studied in vitro and show potential as selective T3S inhibitors in several Gram-negative pathogens besides Y. pseudotuberculosis. The data obtained suggest that this inhibitor class targets a conserved protein in the secretion apparatus. In cell-based ex vivo infection models T3SS was inhibited to the advantage of the infected eukaryotic cells. The salicylanilides and 2-arylsulfonamino-benzanilides have been further investigated by statistical molecular design (SMD) followed by synthesis and biological evaluation in the T3SS linked reporter gene assay. Multivariate QSAR models were established despite the challenges with data obtained from assays using viable bacteria. Our results indicate that this SMD QSAR strategy is powerful in development of virulence inhibitors targeting the T3SS.

The ever increasing demands on today's engine performance and emissions control is forcing the automotive industry to make use of innovative solutions. One of these is to apply the technology of VNT turbos on commercial petrol vehicles. When using a VNT turbo, the aspect ratio of the turbine can be altered while driving to suit the current operating window. In order to actually gain performance while using a VNT, the vanes have to be properly controlled using a suitable control strategy. In this project, direct collocation have been utilized through the usage of YOP which is an adaptation of CasADi in MATLAB to solve non-linear optimization problems. Comprehensive models of the turbocharger and the cylinders have been built and validated to properly represent a VEP4 LP engine from AUROBAY. The models are implemented in YOP to create and simulate different OCPs using the turbo speed as state and position of the vanes as control signal. With this model in YOP together with the air mass flow per second as reference, a good reference following together with decent values for relevant parameters can be accomplished. Other objective functions such as minimum time and maximal volumetric efficiency are also investigated in the project which yield likewise results. From the results it can be concluded that this type of model and control strategy can be used with success when studying optimal control of a VNT turbo.