A potent inhibitor of 2C-methyl-D-erythritol 2,4-cyclodiphosphate synthase (IspF) has the potential to serve as a new class of antibiotic. In this project, we explored the development of such an inhibitor using a mixed experi-mental/computational approach. A promising lead was identified using chemical intuition and previously published re-search, but it failed to show significant activity toward IspF. The computational results explained this unexpected lack of inhibition. The lead compound cannot adopt the anticipated bidentate binding motif without substantial steric and angle strain.