Role and mechanism of hexyl-aminolevulinate ethosome-mediated antimicrobial photodynamic therapy in reversing fluconazole resistance in Nakaseomyces glabrata (Candida glabrata).

Abstract

Introduction. Azoles are extensively employed as clinical antifungal agents; however, their long-term and widespread application contributed to the progressive emergence of azole resistance. A significant increase in infections caused by azole-resistant Nakaseomyces glabrata highlights the need for novel therapeutic strategies.Hypothesis/Gap Statement. The efficacy of hexyl-aminolevulinate ethosome-mediated antimicrobial photodynamic therapy (HAL-ES-aPDT) against drug-resistant fungal pathogens, as well as its underlying mechanisms, remains to be elucidated. Our previous studies have demonstrated that HAL-ES-aPDT, which utilizes the photosensitizer HAL-ES, eliminates pathogens via photochemical reactions.Aim. This study aimed to evaluate the effects and mechanisms of HAL-ES-aPDT on clinical isolates of N. glabrata exhibiting varying levels of azole susceptibility, with a focus on changes in resistance and virulence.Methodology. Several clinical isolates of N. glabrata were collected, and the effects and mechanisms of HAL-ES-aPDT treatment on azole-resistant strains were investigated.Results. HAL-ES-aPDT reduced N. glabrata tolerance to environmental stress and reversed azole resistance by inhibiting drug efflux and downregulating genes encoding the target enzymes. It also attenuated in vivo virulence by downregulating the expression of the epithelial adhesin gene EPA1.Conclusion. These results confirm the efficacy of HAL-ES-aPDT against azole-resistant N. glabrata and provide novel mechanistic insights that may facilitate the development of effective therapeutic interventions for resistant fungal infections.