Antifungal resistance: from classical mechanisms to the expanding role of acetyltransferases

Antifungal resistance represents a growing global health challenge, driven by limited therapeutic options, inadequate use of both clinical and environmental drugs, and the remarkable adaptive capacity of fungal pathogens. While resistance has classically been attributed to genetic alterations affecting drug targets and efflux systems, accumulating evidence indicates that regulatory mechanisms play a critical role in shaping antifungal susceptibility. This review highlights that acetyltransferases constitute important and active components of antifungal resistance, operating through multiple integrated mechanisms. Notably, recent studies have extended this framework by identifying the direct enzymatic inactivation of antifungal agents by acetyltransferases, which emerges as an additional resistance mechanism and establishes a functional parallel with antibiotic acetylation in bacteria. These findings highlight acetyltransferases as clinically relevant drivers of antifungal resistance and suggest that targeting these enzymes may enhance the efficacy of existing antifungal therapies and reduce treatment failure.