The development of new antibiotics faces a severe crisis inter alia owing to a lack of innovative chemical scaffolds with activities against Gram‐negative and multiresistant pathogens. Herein, we report highly potent novel antibacterial compounds, the myxobacteria‐derived cystobactamids 1–3, which were isolated from Cystobacter sp. and show minimum inhibitory concentrations in the low μg mL−1 range. We describe the isolation and structure elucidation of three congeners as well as the identification and annotation of their biosynthetic gene cluster. By studying the self‐resistance mechanism in the natural producer organism, the molecular targets were identified as bacterial type IIa topoisomerases. As quinolones are largely exhausted as a template for new type II topoisomerase inhibitors, the cystobactamids offer exciting alternatives to generate novel antibiotics using medicinal chemistry and biosynthetic engineering. Against multidrug resistance: A novel chemical scaffold with very pronounced activity against bacterial topoisomerases has been isolated from myxobacteria. Cystobactamid 919‐2, as the most active derivative, is a potent antibacterial agent against numerous pathogens, including some Gram‐negative species, such as E. coli and A. baumannii (see Scheme; rel and SC denote relaxed and supercoiled E. coli DNA, respectively).