Targeting Antifungal Resistance in Candida: Non-genetic variation, Epigenetic Modulation, Efflux Pump Inhibition, and Combination Therapeutics

Fungal pathogenesis represents a growing challenge to global health, agriculture, and ecological stability, particularly as opportunistic infections caused by Candida species become increasingly difficult to treat due to rising antifungal resistance. Candida albicans and emerging non-albicans species have evolved sophisticated mechanisms - non-genetic variation, epigenetic regulation, efflux pump activation, and biofilm formation - that enable rapid adaptation to antifungal stress. Recent epidemiological data indicate a worrying trend in multidrug-resistant Candida auris infections with limited treatment options, underlining an urgent need for novel strategies that target resistance mechanisms beyond conventional drug development. Advances in high-throughput genomics, transcriptomics, and epigenetic profiling have begun to unveil the complex regulatory networks underpinning antifungal tolerance. However, these insights have yet to be fully integrated into translational research capable of delivering effective therapeutics. Understanding and targeting the interplay between non-genetic variation, genetic, epigenetic, and cellular responses to antifungal agents remain critical frontiers in fungal pathogenesis research.This Research Topic aims to explore innovative mechanisms and therapeutic strategies to overcome antifungal resistance in Candida species. The focus is on understanding how non-genetic variation and epigenetic modulation influences resistance phenotypes, the functional characterization of cellular efflux systems, and the development of rational combination therapies that enhance antifungal efficacy while minimizing toxicity. The objective is to advance fundamental knowledge of antifungal adaptation and resistance evolution, identify druggable molecular targets, and foster translational approaches that address clinical and agricultural challenges associated with Candida infections. Key questions include: Which kind of non-genetic variation causes antifungal drug resistance? How do epigenetic regulators mediate reversible drug tolerance? What are the synergistic effects of combined antifungal agents targeting efflux and metabolic pathways? Can host-pathogen interactions be leveraged to sensitize resistant strains?To gather further insights within the field of Candida antifungal resistance and therapeutic innovation, we welcome articles addressing, but not limited to, the following themes:- Mechanisms of non-genetic variation that confer antifungal resistance- Epigenetic mechanisms underlying antifungal resistance in Candida species- Regulation and inhibition of efflux pumps as therapeutic targets- Mechanistic studies of combination antifungal and immunomodulatory treatments- Molecular and cellular responses to antifungal stress and drug adaptation- Omics-based modeling of resistance evolution and drug susceptibility- Host-pathogen interactions affecting antifungal efficacy- Development of novel compounds and natural product derivatives targeting resistant Candida strains- Preclinical or heterologous models to evaluate combination drug therapiesWe welcome submissions across research and review articles, short communications, methods papers, and hypothesis-driven studies that advance understanding and therapeutic intervention of antifungal resistance in Candida, aligning with the goals of the Fungal Pathogenesis section and broader Sustainable Development Goals—SDG 3 (Good Health and Well-being) and SDG 15 (Life on Land). Topic editors: Hironobu Nakayama, Susumu Kajiwara Source: https://www.frontiersin.org/research-topics/82331/targeting-antifungal-resistance-in-candida-non-genetic-variation-epigenetic-modulation-efflux-pump-inhibition-and-combination-therapeutics