Inhibitors of bacterial two-component signalling systems

Bacterial two-component regulatory systems (TCS) play a pivotal role in the process of infection. These signal transduction systems enable bacterial p athogens to mount an adaptive response and cope with diverse environmental stresses, including nutrient deprivation, antibiotic onslaught and phagocyt osis. Interest in these systems as novel bacterial targets has been rekindl ed by the recent discovery of several essential systems in important Gram-p ositive and Gram-negative pathogens. Several series of TCS inhibitors deriv ed from broad screening approaches have been reported in the literature, ho wever, most appear to suffer from poor selectivity, excessive protein bindi ng and/or limited bioavailability. Consequently, pharmaceutical chemists ha ve turned to alternate strategies, such as the design of substrate-based in hibitors, the generation of combinatorial libraries and the isolation of na tural products, to identify inhibitors with more desirable properties. Rece nt structural studies of the histidine protein kinase and response regulato r proteins that constitute TCS may provide a foundation for a structure-bas ed design approach to TCS inhibitors.