Molecular structure of Bacillus anthracis Edema factor

Boston Biomedical Research Institute
posted on 05/12/2011

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Summary of the Invention: Edema Factor (EF) is a calmodulin (CaM) activated adenylyl cyclase exotoxin secreted by Bacillus anthracis, the bacterium that causes anthrax. Together with two other bacterial proteins, EF is necessary for all pathogenic effects of Bacillus anthracis.
This invention resolves molecular structure of EF to a high resolution. Specifically, the crystal structures of a) EF without substrate; b) EF-calmodulin complex without substrate; and c) EF-calmodulin complex with 3’dATP, a non-cyclizable substrate analog have been determined by X-ray crystallography.
This invention relates to the use of the structures of edema factor without substrate, edema factor-calmodulin complex, and any of its homologues, mutants and/or co-complexes of such structures to design inhibitors of calmodulin activation of EF. Such inhibitors will protect humans against anthrax infection much more efficiently then existing antibiotics which inhibit bacterial replication, yet fail to treat systematic infections resulting from Bacillus anthracis inhalation.
In addition to Bacillus anthracis, two other bacteria, Bordetella pertussis (Whooping cough) and Pseudomonas aeruginosa (various nosocomial infections), have exotoxins with adenylyl cyclase activity. Consequently, developing an inhibitor against EF may facilitate the development of inhibitors against these other exotoxins and provide treatment for two additional diseases.