Here we demonstrate that V. cholerae infection of D. melanogaster exhibits the following parallels to human disease: (i) ingestion of V. cholerae produces an intestinally-localized, lethal infection in the fly that is dependent on cholera toxin; (ii) host susceptibility is dependent on Gsα, adenylyl cyclase, and the Drosophila KCNN4 channel homolog; and (iii) clotrimazole, an inhibitor of the human KCNN4 channel, protects the fly against infection. This evidence concerns the gene GNAS and infection.