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Biofilm formation is dependent on the two\u2010component 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\u2010based 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\u2010driven 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\u2010spectrum 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\u2010depth review of the significance and challenges of TCS as emerging drug targets.<\/jats:p>","DOI":"10.1002\/ddr.70368","type":"journal-article","created":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T15:05:37Z","timestamp":1786979137000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Two\u2010Component System as Drug Target: Is It a Bandwagon or a Breakthrough?"],"prefix":"10.1002","volume":"87","author":[{"given":"Akanksha","family":"Haldiya","sequence":"first","affiliation":[{"name":"Amity Institute of Biotechnology Amity University Rajasthan Jaipur India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Himanshi","family":"Kain","sequence":"additional","affiliation":[{"name":"Amity Institute of Biotechnology Amity University Rajasthan Jaipur India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Poonam","family":"Kumari","sequence":"additional","affiliation":[{"name":"Amity Institute of Biotechnology Amity University Rajasthan Jaipur India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vijay Kumar","family":"Srivastava","sequence":"additional","affiliation":[{"name":"Institute of Science Nirma University S\u2010G Highway Ahmedabad India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vinay","family":"Sharma","sequence":"additional","affiliation":[{"name":"Amity Institute of Biotechnology Amity University Rajasthan Jaipur India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S. 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