Structural and biochemical characterization of Class I and Class III adenylyl cyclases from microbial pathogens

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Adenylyl cyclases (ACs) synthesize the ubiquitous second messenger cyclic AMP (cAMP) from ATP. In pathogenic microbes, cAMP is often involved in the regulation of virulence mechanisms. Microbes contain AC enzymes of the Class I and Class III subfamilies. Several microbial ACs of the structurally well studied Class III have been confirmed as drug targets, and the low conservation within this family renders specific inhibition of individual Class III enzymes possible. No structural information is yet available for the AC Class I, which is unique to bacterial organisms and thus enables even more specific inhibition of signaling systems of bacterial pathogens.We propose to study the structural details that differentiate CyaB, a confirmed drug target in the pathogen Pseudomonas aeroginosa, from Class III ACs of its human host. Using this information, modifications improving existing inhibitors as well as completely novel compounds will be identified. Further, we propose to solve the first crystal structure of a Class I AC as a representative of this conserved family. The structural data will again be used for the development of inhibitors, which should result in drugs affecting only the Class I AC-carrying pathogen with little side effects on the human host.