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Research Areas
EPI screening
Screening of small molecule libraries for drug sensitizing properties and for enhanced dye accumulation is an option to identify potentially useful bacterial efflux pump inhibitors (EPIs). Methods of screening will vary according to species and drugs selected for sensitizing effects. We are seeking to optimize the methods and find new dyes useful in large-scale fluorescence-based accumulation or efflux screening for Enterobacteriaceae, S. aureus and mycobacteria.
AcrB mutational analysis
MDR efflux pumps pump out a variety of chemically unrelated drugs out of the cell, a property which needs a particular structure to provide this broad specificity. There are reports describing binding pockets within MDR efflux pumps with flexible binding sites that, in theory, might be utilized by EPIs for efflux retardation or inhibition by steric hindrance, for example. We use an in vitro mutagenesis approach to identify amino acid residues in AcrB (the most important MDR efflux pump in E.coli) relevant for substrate binding and EPI resistance.
MDR efflux as virulence factor
Bacterial MDR efflux pumps do not only decrease drug susceptibility. They are also associated with altered virulence in certain species. For P. aeruginosa, E. coli and S. aureus we are using clinicoepidemiological data and laboratory analyses (pump activity and gene expression studies) to assess the relationship between outcome of the infection and efflux pumps, and we are trying to establish simple models such as a C. elegans model to study this relationship in further detail.
MDR clinical epidemiology and interventions
Bacterial multidrug resistance has been an emerging clinical problem, and there is some indication that the use of particular drugs or drug classes might be ecologically more risky than others to promote multidrug resistance. We are investigating through ecological studies the potential impact of antibiotic policy changes in given settings (such as a hospital) on drug resistance evolution and burden.
