Comprehensive profiling of lysine lactylation in Candida albicans and exploratory analysis of fluconazole tolerance associations.

Candida albicans is the primary pathogen of invasive candidiasis in most regions worldwide, but the therapy options for C. albicans infections are limited, and drug tolerance further exacerbates the treatment challenges. Lysine lactylation (Kla), a recently identified post-translational modification (PTM), is observed in numerous organisms; however, the role of Kla in C. albicans remains unknown. Hence, we report the first proteomic analysis of this specific modification in C. albicans and discuss its potential roles in drug tolerance of C. albicans. Altogether, 7,233 lactylation sites on 1,608 lactylated proteins were identified in C. albicans, with the highest degree of lactylation among the species studied so far. The further bioinformatics analysis revealed that the lactylated proteins were implicated in a variety of cellular functions with diverse subcellular localizations. Additionally, we found a unique survival mode of tolerant cells in the presence of fluconazole, which will be subject to a more thorough investigation in our future studies. This paper is the first report on the lactylome of Candida spp. and provides a reliable foundation for further research on Kla in C. albicans and other human pathogens.

Importance: This is the first report on the lactylome of Candida spp., and it provides some valuable insights for further research on lactylation in C. albicans and other human pathogens. Moreover, the observations in tolerant cells have prompted plausible hypotheses regarding the potential role of lactylation in mediating C. albicans tolerance to fluconazole, thereby offering a conceptual framework for subsequent investigations. Notably, fungal tolerance to azoles, a concept distinct from resistance, represents a critical phenomenon in C. albicans with profound clinical implications, as it directly correlates with therapeutic failure and persistent infections.