Bacterial Signal Transduction: Two-Component Signal Transduction as a Model for Therapeutic Intervention

Bacterial signal transduction is a complex and poorly understood process that enables bacteria to grow, divide, withstand physiological insult and exert metabolic changes that allow them to adapt to and survive in their environment. These systems permit the organism to respond to biochemical or physical signals from its surroundings and within itself, in order to accomodate a dynamically changing environment. One of the major signal transduction systems in bacteria is the two-component signal transduction system, composed of hundreds of functionally diverse, but structurally-related, protein-pair motifs which facilitate the transfer of phosphate groups from ATP to key effector proteins. It is the level of phosphorylation of two-component signal-transducing proteins which ultimately controls gene expression in the bacterium. Acting upon demand, this unique histidyl-aspartyl phosphotransfer system enables the bacterium to quickly alter gene expression for processes under “stress”, allowing the bacterium to survive in virtually any natural environment. As the story of two-component signal transduction unfolds, it is becoming increasingly clear that these systems play a major part in allowing organisms to survive in the host as opportunistic pathogens. Although not a single microbial signalling pathway has been successfully exploited for drug intervention to date, an awakening of the understanding of their potential will lead to opportunity and success. Although primarily a “non-essential” process in most bacteria, the two-component signal transduction system represents tremendous potential for pharmaceutical intervention, as the understanding of the in vivo “essentiality” of many of these two-component signal transduction systems for pathogenicity continues to develop.