Pseudomonas aeruginosa: From acute virulence to chronic persistence—mechanisms and therapeutic implications

Pseudomonas aeruginosa (PA) is a gram-negative opportunistic bacterium that frequently causes nosocomial infections. Its capacity to evolve from an acute infection characterized by rapid tissue damage to a persistent chronic infection that is difficult to eradicate leads to reduced antibiotic efficacy, disease deterioration, and poor prognosis. This review dissects two major driving forces—intrinsic regulatory networks and adaptive evolution under selective pressures underlying this transition—defines the central role of biofilms, and explores therapeutic implications. Under pressures such as the immune system and antibiotics, PA undergoes lifestyle transition, metabolic reprogramming, and immune evasion through the quorum-sensing (QS), Gac-Rsm, and c-di-GMP networks. Based on these mechanisms, therapeutic approaches targeting the acute-to-chronic infection transition have been developed, including anti-virulence therapy, anti-biofilm strategies, anti-persister strategies, immunomodulatory therapy, and phage therapy. Although these novel therapeutic strategies have demonstrated substantial potential in preclinical models of chronic persistent infections, their clinical applications remain limited. Future studies should further elucidate the dynamic crosstalk among the core regulatory systems within the host microenvironment and develop intervention strategies targeting key nodes in the acute-to-chronic transition. Such advances hold considerable promise for eradicating chronic persistent infections and ultimately improving clinical outcomes for patients.