Table 2.
Detailed mechanisms of antifungal resistance in Candida biofilms.
| Mechanism | Molecular/cellular components | Effect on antifungal susceptibility | Drug classes affected | References |
|---|---|---|---|---|
| Extracellular Matrix | β-1,3/1,6-glucans, mannan-glucan complexes, eDNA, matrix proteins, extracellular vesicles | ECM binds/sequesters drugs, slows diffusion into deeper layers, and protects embedded cells | Azoles, polyenes, echinocandins | Pierce et al., 2017; Nett and Andes, 2020; Roy and Gow, 2023 |
| Efflux Pumps | CDR1, CDR2 (ABC family); MDR1 (MFS family) | Active export of azoles; increased pump expression in biofilms increases drug efflux | Mainly azoles | Atriwal et al., 2021; Ren et al., 2024; Kaur and Nobile, 2023 |
| Stress-Response Pathways | Hsp90 chaperone, calcineurin, Crz1 transcription factor, heat-shock proteins | Stabilization of stress proteins; cell-wall repair; survival under antifungal stress | Azoles, echinocandins, polyenes | Cowen, 2009; Gong et al., 2017; O’Meara et al., 2017 |
| Membrane & Ergosterol Remodeling | ERG genes, altered ergosterol content, and membrane fluidity regulators | Reduced binding of azoles/polynes; altered permeability; increased membrane rigidity | Azoles, polyenes | Kaur and Nobile, 2023; Atriwal et al., 2021 |
| Metabolic Heterogeneity & Quiescence | Hypoxic zones, nutrient-deprived layers, slow-growers, dormant cells | Fungicidal drugs are ineffective against slow-growing cells; survival of metabolically inactive phenotypes | Mostly fungicidal drugs (polyenes, echinocandins) | Wall et al., 2019; Pierce et al., 2017 |
| Matrix-associated Extracellular Vesicles | EV cargo: polysaccharides, enzymes, β-glucan modifying factors | Reinforce matrix structure; deliver materials for ECM synthesis | All antifungal classes | Zarnowski et al., 2014; Mathé, and Van Dijck, 2013 |
| Cell-wall Remodeling Pathways | PKC–MAPK pathways, chitin synthase upregulation | Thickened cell wall reduces drug penetration; compensatory chitin increases echinocandin tolerance | Mainly echinocandins | LeBlanc et al., 2020; Robbins et al., 2011 |
| Oxidative Stress Defense | SODs, catalases, glutathione pathways | Detoxify ROS generated by antifungals; enhance survival | Polyenes, some azoles | da Silva et al., 2021; Wuyts et al., 2018 |
ECM, Extracellular Matrix; eDNA, Extracellular DNA; EVs, Extracellular Vesicles; ABC, ATP-Binding Cassette; MFS, Major Facilitator Superfamily; CDR, Candida Drug Resistance; MDR1, Multidrug Resistance 1; Hsp90, Heat Shock Protein 90; Crz1, Calcineurin-Responsive Zinc-finger 1; ERG genes, Ergosterol Biosynthesis Genes; PKC, Protein Kinase C; MAPK, Mitogen-Activated Protein Kinase; SODs, Superoxide Dismutases; ROS, Reactive Oxygen Species.