Description
The widespread use of antibiotics in human healthcare and in veterinary medicine has inevitably led to the selection of resistant strains in every major group of pathogenic bacteria, but up until the last decade scientific achievements were able to keep ahead. From the 1940s to 1990 new antibiotics were developed faster than resistance but this is no longer the case and, we are seeing an alarming increase in the spread of resistant pathogens. Therefore, the search for new antibacterial drugs directed toward new targets is currently an urgent necessity.
Two-component signal transduction systems (TCS) appear to be a fundamental constituent of the regulatory organisation in bacteria and they frequently control the expression of virulence factors and adaptive responses. TCS comprise a histidine kinase (HK) in the membrane that senses an environmental stimulus and a cognate response regulator (RR) in the cytoplasm that controls gene expression through binding to DNA promoter regions. The TCS proteins exhibit a high homology to each other across Gram-positive and Gram-negative species, and they represent the only known virulence mechanisms that are common to a variety of pathogens. Because of these features of the TCSs, and their absence in mammalian cells, they are viewed as an attractive target for anti-infective intervention. Among them, the YycFG is the only TCS essential for viability in several Gram-positive bacteria including the major pathogens Streptococcus pneumoniae, Streptococcus pyogenes and Staphylococcus aureus.
Our group is studying the mechanism of regulation and the mode of action of YycFG on essential gene expression by a global genomic and proteomic approach as well as by DNA-protein and protein-protein interaction studies. The S. pneumoniae RR YycF, and the HK YycG are being used as model systems, with the aim of developing a new class of anti-infective drugs. This work programme is within the framework of the project “Design of Antibacterial Drugs Based on Unexplored Genetic Structures” led by Laboratorios SALVAT (Barcelona) in collaboration with the Key Drug Prototyping company (Amsterdam, The Netherlands), the group of Prof. Jerry Wells (University of Wageningen, The Netherlands ) and our own group. This consortium has been given the EUREKA label 3554-DEADBUGS, a hallmark which distinguishes it as a pan-European initiative capable of developing innovative products, processes and services.
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