Two-component regulatory systems can detect a broad range of environmental signals, such us light, oxygen, pH, temperature, and even some heavy metals and organic contaminants . Many types of TCRS-based environmental biosensors have been reported, but only a few heavy metal- and organic pollutant-based sensors have been developed to date (Fig. 2). Bacteria use several TCRSs to sense specific heavy metals. Because heavy metals are cations that are both toxic and essential, bacterial cells use TCRSs to regulate the homeostasis of these metal cations. A HydHG TCRS (also known as ZraSR) was identified in Escherichia coli that senses and controls the expression of zraP gene encoding zinc efflux protein under high concentrations of Zn2+ and Pb2+ in aerobic condition . HydH protein is tightly bound to the cell membrane and is assumed to be responsible for sensing high periplasmic Zn2+ and Pb2+ concentration. Then, in the presence of a phosphoryl donor, HydG binds to the intergenic region within zraP-hydHG resulting in the upregulated expression of ZraP . Likewise, the CusRS (ylcA, ybcZ) TCRS found in E. coli K-12 is responsive to Cu2+ ions and is required for the inducible expression of pcoE, belonging to the plasmid-borne pco operon, the induction of the genes in this operon activates the copper efflux system thereby allowing the excess Cu2+ to exit the cell . Some TCRS can regulate the expression of several specific genes in an operon or a whole operon. The SilRS TCRS increases the resistance of Salmonella enterica to silver cations through the coupled sensing and activation expression of the periplasmic silver-specific binding protein, SilE encoded by silE gene and two parallel efflux pumps, SilP and SilCBA . This is also in the case of NrsSR TCRS identified in Synechocystis sp. PCC6803. NrsSR senses Ni2+ and Co2+ ions and regulates the expression of the nrsBACD operon that encodes proteins involved in Ni2+ resistance . In another study, a PfeS/R TCRS senses ferric enterobactin and induces the production of the enterobactin receptor PfeA in Pseudomonas aeruginosa .Fig. 2 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