Figure 3.

Representation of the potentially targetable components of a two-component system (TCS) for preventing MDR. The histidine kinase (HK) sensor senses a generic signal (dark red thunderbolt) via the signal peptide linker (SPL), which links two transmembrane (TM) domains. The other elements forming the HK are a signal transduction domain (STD), a cytoplasmic sensor domain (CSD), an ATP catalytic domain (ATP), and a dimerization histidine phosphotransfer domain (DHp). The response regulator (RR) is composed of the receiver domain (RD) and the effector domain (ED). The phosphorylation (P) of the HK is followed by the transfer of the phosphoryl-group (P) to the RD that induces the ED to bind to its target genes (row structure) and regulate their expression. The tipless arrows indicate the sites of action of the TCS inhibitors: (A) an inhibitor that can avoid TCS activation by its usual stimulus; (B) an inhibitor that can block HK dimerization; (C) an inhibitor targeting the site for ATP binding; (D) an inhibitor that can prevent the ATP from binding to the RD; (E) an inhibitor that can reduce or avoid the RR binding to antibiotic resistance-mediated genes.