A natural product inspired fragment-based approach towards the development of novel antibacterial agents

The discovery of new antibiotics with novel modes of action to combat antimicrobial resistance (AMR) is ofvital importance. The natural product simocyclinone D8 (SD8) is a potent inhibitor of DNA gyrase. Its bifunctionalstructure and novel mode of action serve as an inspiring lead for antibiotic development. Hereinwe describe a proof of principle fragment-based approach towards the development of a new class ofcoumarin-quinolone hybrids. We demonstrate that the coumarin moiety is required for the observed inhibitoryactivity (IC50 ∼ 3 μM) of the hybrid compound, which is in part mediated through stabilisation of acleaved-DNA intermediate.