From comparative genomics to systems biology - unravelling novel principle virulence mechanisms in pathogenic spore-forming bacteria

In the past decade, our research group has been involved in the characterization of virulence mechanisms in Bacillus cereus group bacteria. Here we propose to study two processes connected to development of resistance to antimicrobial compounds - the func tion and cellular response of multidrug resistance proteins, and the formation of microbial biofilms. These are not only fundamental processes linked to the survival of these free-living bacteria in soil or other natural habitats where they may constitute reservoirs for disease, but may be important in vivo, contributing to the variety of human and animal diseases observed. Biofilm formation is a cellular mechanism known to confer adhesion properties and resistance to antimicrobial compounds in many bacte ria, and may thus be an important property in bacterial virulence. Isolates from the B. cereus group are known to have the ability to form biofilm, but a systematic molecular characterization of factors involved has not been reported. Furthermore, the B. cereus group currently constitutes the bacterial group with the highest number of fully sequenced genomes (21 strains) and genome comparisons indicate that these bacteria encode the highest number of putative multidrug transporter genes known to date. In this project, bioinformatics and comparative genomics analyses form the base for functional experiments to: 1) analyze molecular and gene regulatory aspects of biofilm formation, including the dissection of genes involved in the process, and 2) investigat e the functional role of the multitude of multidrug transporter proteins found in the B. cereus group bacteria, with emphasis on the MDRs conserved in all sequenced genomes within the B. cereus group. The project will be based on a systems biology approac h combining bioinformatic, transcriptional, and structural analyses, as well as proteomics aspects, to identify regulatory networks and characterize global cell response systems to external stimuli.