Progress Overview of Bacterial Two-Component Regulatory Systems as Potential Targets for Antimicrobial Chemotherapy

Abstract

Bacteria adapt to changes in their environment using a mechanism known as the two-component regulatory system (TCS) (also called "two-component signal transduction system" or "two-component system"). It comprises a pair of at least two proteins, namely the sensor kinase and the response regulator. The former senses external stimuli while the latter alters the expression profile of bacterial genes for survival and adaptation. Although the first TCS was discovered and characterized in a non-pathogenic laboratory strain of Escherichia coli, it has been recognized that all bacteria, including pathogens, use this mechanism. Some TCSs are essential for cell growth and fitness, while others are associated with the induction of virulence and drug resistance/tolerance. Therefore, the TCS is proposed as a potential target for antimicrobial chemotherapy. This concept is based on the inhibition of bacterial growth with the substances acting like conventional antibiotics in some cases. Alternatively, TCS targeting may reduce the burden of bacterial virulence and drug resistance/tolerance, without causing cell death. Therefore, this approach may aid in the development of antimicrobial therapeutic strategies for refractory infections caused by multi-drug resistant (MDR) pathogens. Herein, we review the progress of TCS inhibitors based on natural and synthetic compounds.

Keywords: drug resistance; environmental response and adaptation; histidine kinase; infection control; response regulator; two-component regulatory system; virulence.

Figure 1

Two-component regulatory system (TCS) in bacteria. When the membrane-bound homo-dimeric sensor kinase senses a particular environmental stimulus, the conserved histidine residue (H) in the cytoplasmic sensor domain of this protein is phosphorylated (P) (termed auto-phosphorylation), then transfers its phosphate group to the conserved aspartate residue (D) in the receiver domain of the cognate response regulator. The kinase activity depends on ATP which is bound to the catalytic domain (CA). The phosphorylated response regulator forms a homo-dimer, then the helix-turn-helix domain (HTH) of the response regulator binds to particular DNA sequences on or close to the promoter of target genes.

Figure 2

Chemical structures of representative sensor kinase inhibitors.

Figure 3

Chemical structures of representative response regulator inhibitors.