Surface-enhanced Raman scattering (SERS) spectroscopy has been applied to detect the interaction of the FtsZ protein from Escherichia coli, an essential component of the bacterial division machinery, with either a soluble variant of the ZipA protein (that provides membrane tethering to FtsZ) or the bacterial membrane (containing the full-length ZipA naturally incorporated), on silver-coated polystyrene micrometer-sized beads. The engineered microbeads were used not only to support the bilayers but also to offer a stable support with a high density of SERS hot spots, allowing the detection of ZipA structural changes linked to the binding of FtsZ. These changes were different upon incubating the coated beads with FtsZ polymers (GTP form) as compared to oligomers (GDP form) and more pronounced when the plasmonic sensors were coated with natural bacterial membranes.