A bidrectional affinity system was used to screen for marine natural products that bound to Escherichia coli proteins. A system was developed and applied to isolated the natural product sceprin from an Agelas conifera extract and its affinity partner MreB from E. coli lysate. The use of dual immunoaffinity fluorescent (IAF) tag permitted this process to coimmunoprecipitate the bacterial equivalent of actin, MreB, from E. coli lysate. MreB was subsequently validated as a target for sceptrin using a resistance mapping approach. The combination of these studies suggests that natural products and their protein targets can be isolated in concert using a melody of forward and reverse affinity matrices. While the structure of sceptrin was elucidated by NMR analysis, the bulk of effort was conducted without knowing the structure of the natural product, thereby elevating a key bottleneck in the development of high-throughput methods for natural product discovery.