Two‐Component System as Drug Target: Is It a Bandwagon or a Breakthrough?

MDR ESKAPE pathogens are the leading cause of hospital-acquired infections (HAIs) that resist most antibiotics and form biofilms. Biofilm formation is dependent on the two-component system (TCS), which regulates virulence traits including adhesion to host tissues, evasion of innate immunity, the synthesis of exopolysaccharides, and antibiotic resistance. TCS sense environmental stimuli such as pH, osmotic pressure and antimicrobial peptides. They regulate gene expression to promote bacterial survival and persistence during infection. TCS represents a contemporary and novel pathway for the advancement of targeted, adjuvant-based options to fend off infections caused by ESKAPE pathogens. Targeting TCS may improve drug penetration and reduce resistance pressure, although challenges remain due to their structural conservation, regulatory complexity, and mutation-driven resistance. However, there are several limitations in targeting TCS for drug development like TCS not always being essential for bacterial viability, structural homologies between TCS are not sufficient for broad-spectrum inhibitors, sometimes TCS can be involved in complex and essential regulatory networks and can evolve resistance mechanisms by mutations. To further investigate this paradox, we implemented comprehensive computational and phylogenetic analyses of selected ESKAPE TCS. The findings from this investigation form the basis for our in-depth review of the significance and challenges of TCS as emerging drug targets.