Candida parapsilosis Virulence and Antifungal Resistance Mechanisms: A Comprehensive Review of Key Determinants

Abstract

Candida parapsilosis is the second most common Candida species isolated in Asia, Southern Europe, and Latin America and is often involved in invasive infections that seriously impact human health. This pathogen is part of the psilosis complex, which also includes Candida orthopsilosis and Candida metapsilosis. C. parapsilosis infections are particularly prevalent among neonates with low birth weights, individuals who are immunocompromised, and patients who require prolonged use of a central venous catheter or other indwelling devices, whose surfaces C. parapsilosis exhibits an enhanced capacity to adhere to and form biofilms. Despite this well-acknowledged prevalence, the biology of C. parapsilosis has not been as extensively explored as that of Candida albicans. In this paper, we describe the molecular mechanistic pathways of virulence in C. parapsilosis and show how they differ from those of C. albicans. We also describe the mode of action of antifungal drugs used for the treatment of Candida infections, namely, polyenes, echinocandins, and azoles, as well as the resistance mechanisms developed by C. parapsilosis to overcome them. Finally, we stress the importance of the ongoing search for species-specific features that may aid the development of effective control strategies and thus reduce the burden on patients and healthcare costs.

Keywords: Candida parapsilosis; Candida spp.; antifungal resistance; azoles; biofilm formation; echinocandins; fungal infections; healthcare-related infections; polyenes; virulence attributes.

Figure 1

Illustration of biofilm formation cycle in Candida spp. Biofilm development consists of three stages: an early phase, in which cells adhere to biotic or abiotic surfaces; an intermediate phase, involving cell proliferation and the formation of a mixed population; and, finally, a maturation/dispersion phase, characterized by the production of the extracellular matrix and the massive dispersion of cells. The detachment and dispersion of daughter cells occurs in all stages of biofilm development.

Figure 2

Mechanism of action of antifungals against Candida spp. and mechanisms underlying drug resistance. (A) Polyenes act by forming polyene/ergosterol aggregates, destabilizing the fungal membrane. The action of polyenes can be overcome through mutations in ergosterol biosynthesis genes responsible for altered sterol composition and by the activation of stress response pathways, such as catalase and Hsp. (B) Echinocandins act as noncompetitive inhibitors of (1,3)-β-D-glucan synthase, encoded by FKS genes, causing a depletion of the 1,3-β-glucan in the cell wall. Echinocandin resistance in Candida is associated with mutations in FKS genes and the activation of cell wall stress response mediator pathways, such as Hsp90 and calcineurin (Ca²⁺), increasing the chitin content. (C) Azoles target and inhibit the enzyme lanosterol 14α-demethylase, encoded by the ERG11 gene, leading to the accumulation of toxic sterol. Azole resistance involves: (i) point mutations in the ERG11 gene, which can be responsible for its overexpression and/or the inhibition of enzyme lanosterol 14α-demethylase, due to the decrease in azole–target binding affinity; (ii) mutations in ERG genes involved in the ergosterol biosynthesis pathway, particularly in ERG3; and (iii) increased efflux of the azole drugs from the fungal cell through the overexpression of multidrug efflux pumps. Red T-shaped bars indicate inhibition. Star icon indicates gene mutation.