a Domain structure of bacterial two-component regulatory systems (TCRS). Typical two-component phosphotransfer systems contain a sensor domain and a cytoplasmic response regulator (RRs). b A multi-component phosphorelay system containing the HAMP, PAS, and phosphotransfer domains. The periplasmic metal-sensing receptors sense heavy metals and phosphorylate the HK domain and activate the corresponding RR. The RR activates the synthetic genetic circuit of the TCRS resulting in the expression of the reporter protein. The genetic circuit shown in gray can be developed as a biosensor