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.

Transcriptomic Analysis of Pseudomonas aeruginosa Response to Pine Honey via RNA Sequencing Indicates Multiple Mechanisms of Antibacterial Activity

“…A two-component regulatory system plays a substantial role in the pathogenicity, bacterial adaptation, and biofilm formation [ 75 , 76 ]. The two-component regulatory system KEGG pathway (also called “two-component signal transduction system”) enables bacteria to sense and respond to environmental or intracellular changes [ 77 , 78 ]. In this study, pine honey treatment induced the differential expression of several genes implicated in this pathway ( Figure 4 A).…”

Polymyxins, the last-resort antibiotics: Mode of action, resistance emergence, and potential solutions

“…Considering their role in different physiological processes of the bacterial cell including the development of drug resistance, the TCSs have been explored as novel drug targets (Bhagirath et al 2019 ; Hirakawa et al 2020 ; Tierney and Rather 2019 ; Worthington and Melander 2013 ). Several investigators have attempted to develop novel drugs by screening small molecules against the bacterial TCSs.…”

The Role and Regulatory Network of the CiaRH Two-Component System in Streptococcal Species

“…Novel drugs with modes of action different from conventional antibiotics are urgently needed to combat bacterial infections caused by these pathogens. Because TCSs are widely distributed in bacteria but do not exist in humans, targeting TCSs has been explored as a novel strategy to combat bacterial infections, especially drug-resistant bacterial infections (Worthington et al, 2013;Hirakawa et al, 2020;Rajput et al, 2021). The CiaRH TCS composed of CiaH and CiaR is an important signal transduction system that mediates various streptococcal behaviors, including competence development, biofilm formation, antibiotic resistance, stress tolerance, bacteriocin production, virulence, pathogenesis, cell wall biosynthesis, and autolysis.…”