Methods for the identification of inhibitors of botulinum neurotoxins are described. Cells are provided that are genetically engineered to express peptides that act as a substrate for a botulinum neurotoxin and the provide reporting groups. Spacer sequences between the reporting groups serve to optimize energy transfer between the reporting groups. Characterization of the energy transfer-dependent signal prior to and following exposure to a botulinum neurotoxin in the presence of a candidate inhibitor provides a measure of the effectiveness of the candidate inhibitor.