Echinocandin Resistance Mechanisms in Candida glabrata

Candida glabrata has emerged as a leading cause of invasive candidiasis, in part owing to its remarkable ability to acquire resistance to the echinocandin class of antifungals, which target the 1,3-β-D-glucan synthase complex in the fungal cell wall. The primary mechanism of high-level resistance involves point mutations in the FKS1 and FKS2 genes encoding subunits of the glucan synthase enzyme, which reduce drug binding and raise minimum inhibitory concentrations. Beyond target alterations, C. glabrata can adopt a drug-tolerant persister state under stress, allowing survival of a subpopulation without permanent genetic change. A hypermutable or “mutator” phenotype, often driven by defects in mismatch repair genes such as MSH2, accelerates the emergence of both echinocandin and multidrug resistance. Additional non-target mechanisms—such as changes in sphingolipid biosynthesis that alter membrane composition, compensatory cell wall remodelling and activation of stress signalling pathways including Hsp90-calcineurin—also modulate susceptibility. The convergence of these mechanisms underlines the global challenge posed by C. glabrata, emphasising the need for robust surveillance, stewardship of existing drugs and innovative combination or sequential therapies to preserve echinocandin efficacy.

Research from Nature Portfolio

Recent studies have elucidated how C. glabrata persister cells arise within host phagocytes. Internalisation by macrophages induces oxidative‐stress-mediated drug tolerance, expanding a reservoir from which FKS mutants emerge; these findings suggest that alternating or combining echinocandins with agents such as amphotericin B may eradicate intracellular reservoirs and limit resistance. Complementing this, foundational work on the mutator phenotype revealed that defects in the MSH2 mismatch repair gene are prevalent in clinical isolates and correlate with rapid acquisition of resistance to both echinocandins and azoles. Identifying strains with an active mutator genotype may inform more aggressive or tailored antifungal regimens and impact long-term patient management.

Echinocandin Resistance Mechanisms in Candida glabrata publication trend

The graph below shows the total number of articles in echinocandin resistance mechanisms in candida glabrata across all publications each year (not limited to Nature Index journals).

Technical terms

1,3-β-D-glucan synthase (GS): Enzyme complex responsible for synthesising β-glucan in the fungal cell wall, constituting the target of echinocandin drugs.

FKS mutations: Point mutations in the FKS1 and FKS2 genes encoding GS subunits that diminish echinocandin binding and elevate resistance.

Drug tolerance (persister state): A reversible, non-proliferative state in which a subpopulation of cells survives lethal drug exposure without heritable resistance mutations.

Mutator phenotype: A condition of elevated mutation rate due to defects in DNA mismatch repair genes (e.g. MSH2), accelerating emergence of antifungal resistance.

References

1. Macrophage internalization creates a multidrug-tolerant fungal persister reservoir and facilitates the emergence of drug resistance. Nature Communications (2023).
2. Evolutionary dynamics in gut-colonizing Candida glabrata during caspofungin therapy: Emergence of clinically important mutations in sphingolipid biosynthesis. PLOS Pathogens (2024).
3. Antifungal susceptibility, molecular epidemiology, and clinical risk factors of Candida glabrata in intensive care unit in a Chinese Tertiary Hospital. Frontiers in Cellular and Infection Microbiology (2024).
4. Population genomic analyses reveal high diversity, recombination and nosocomial transmission among Candida glabrata (Nakaseomyces glabrata) isolates causing invasive infections. Microbial Genomics (2024).
5. Prevalent mutator genotype identified in fungal pathogen Candida glabrata promotes multi-drug resistance. Nature Communications (2016).
6. Fungal Resistance to Echinocandins and the MDR Phenomenon in Candida glabrata. Journal of Fungi (2018).