Mechanisms of Azole Resistance in CandidaA Narrative Review

Abstract

Candida species, opportunistic fungal pathogens, pose a significant threat to human health, and the emergence of drug-resistant Candida strains has become a major concern in clinical settings, limiting the efficacy of antifungal therapies. Azoles are a class of antifungal agents that play a crucial role in the management of fungal infections. They have several advantages which contributes to their widespread use, like their broad-spectrum activity, availability in systemic and topical formulations, good oral bioavailability, tolerability, target specificity, established efficacy, and low toxicity for long-term prophylaxis. Azole resistance in Candida species poses a significant therapeutic challenge in the management of fungal infections, particularly in immunocompromised individuals. One common mechanism of resistance involves alterations in the target enzyme, cytochrome P450 14-alpha-demethylase (CYP51), which is essential for ergosterol biosynthesis, a crucial component of fungal cell membranes. Mutations in the CYP51 gene can lead to structural changes in the enzyme, reducing its affinity for azoles and thus decreasing their inhibitory effect. Another mechanism involves overexpression of efflux pumps, such as ATP-binding cassette (ABC) transporters and major facilitator superfamily (MFS) transporters. These pumps actively remove azoles from fungal cells, preventing them from reaching effective concentrations and thereby reducing their antifungal activity. A better understanding of the mechanisms underlying drug resistance is crucial for developing effective strategies to overcome this growing problem. This review describes and summarises the mechanisms associated with azole resistance in Candida, exploring the genetic, biochemical, and cellular factors contributing to this phenomenon. Additionally, potential approaches to combat azole resistance are discussed, aiming to pave the way for the development of novel therapeutic interventions.