The discovery of new antibiotics with novel modes of action to combat antimicrobial resistance (AMR) is of vital importance. The natural product simocyclinone D8 (SD8), a potent inhibitor of DNA gyrase with a bi-functional structure and novel mode of action, serves as an inspiring lead for antibiotic development. Herein we describe a proof of principle fragment-based approach towards the development of a new class of coumarin-quinolone hybrids inspired by SD8. We synthesized hybrid compound 4 by tethering a simple coumarin via a 15-Å linker to ciprofloxacin, and prepared two control compounds (aniline-based and linker-only ciprofloxacin) to evaluate the role of the coumarin moiety. Biological assays showed that the efficacy of ciprofloxacin was severely attenuated by the introduction of the linker (compound 18), but activity was restored when the coumarin was present: compound 4 exhibited an IC50 of ~3 µM, comparable to SD8. The aniline control (16) displayed significantly poor inhibition, confirming the coumarin's essential role in activity. Mode-of-action studies demonstrated that compound 4 stabilizes the gyrase-DNA covalent complex, similar to ciprofloxacin. Each constituent fragment (coumarin or linker-modified ciprofloxacin) showed poor inhibition individually, indicating a synergistic effect is vital for the observed activity. These results illustrate that the coumarin fragment contributes to the inhibitory efficacy of hybrid 4, and the unfunctionalized scaffold provides a suitable template for future structure-activity relationship studies. This proof of concept work serves as an example of a natural product-guided fragment-based approach to developing novel inhibitors of DNA gyrase.