Antimicrobial photodynamic therapy across ESKAPE pathogens: Efficacy, limitations, and a pathogen-adapted framework...

Multidrug-resistant (MDR) bacteria belonging to the ESKAPE group-Enterococcus spp., Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter spp.-represent some of the most urgent threats to global health. These pathogens are major causes of healthcare-associated infections and are characterized by extensive antibiotic resistance, biofilm formation, persistence phenotypes, and multiple virulence mechanisms that limit the effectiveness of conventional antimicrobial therapies. Antimicrobial photodynamic therapy (aPDT) has emerged as a promising non-antibiotic approach based on the light activation of photosensitizers, leading to the generation of reactive oxygen species (ROS) that induce multi-target oxidative damage. This review evaluates the current evidence supporting aPDT against ESKAPE pathogens and examines the biological and therapeutic factors that influence treatment outcomes. Across ESKAPE pathogens, aPDT frequently achieved clinically relevant antibacterial effects, including reductions of ≥3 log₁₀ CFU under optimized conditions. However, treatment efficacy varied substantially according to bacterial envelope architecture, biofilm organization, and infection accessibility. Gram-positive pathogens generally exhibited higher susceptibility, whereas Gram-negative species-particularly P. aeruginosa-required strategies to overcome outer membrane barriers, biofilm-associated protection, and limited photosensitizer penetration. Beyond direct antimicrobial activity, numerous studies reported biofilm disruption, modulation of virulence-associated pathways, and enhanced susceptibility to conventional antibiotics. Collectively, these findings suggest that aPDT efficacy is determined not only by photosensitizer potency but also by pathogen-specific structural and physiological constraints. Current evidence supports aPDT as a promising adjunctive strategy against MDR ESKAPE pathogens, particularly in localized and accessible infections where effective light delivery can be achieved. The therapeutic performance of aPDT appears to follow a pathogen-dependent gradient shaped by bacterial structure, biofilm complexity, and treatment accessibility. These observations support a pathogen-adapted framework for aPDT development, in which photosensitizer selection, delivery systems, and irradiation strategies are tailored to the biological characteristics of individual pathogens. Future progress will require greater protocol standardization, improved translational models, and well-designed clinical studies to facilitate the integration of aPDT into antimicrobial practice.