Antifungal tolerance in clinical isolates during the development of drug resistance

Abstract

The increasing prevalence of fungal diseases, particularly those caused by Candida albicans, presents a significant challenges for healthcare due to the rising number of immunocompromised individuals. C. albicans, an opportunistic pathogen, often transitions from a harmless commensal organism to a virulent pathogen under conditions of immune suppression, leading to a spectrum of infections from superficial to life-threatening systemic diseases. Despite advancements in antifungal therapies, infections caused by C. albicans remain associated with high mortality rates, highlighting the organism's complex mechanisms for evading host immune responses and developing drug resistance. This study investigates the evolution of drug tolerance and resistance in C. albicans clinical isolates, particularly in the context of fluconazole treatment. The research focuses on understanding the role of aneuploidy, heat shock response, and subpopulation dynamics in the development of tolerance. Through a series of experiments involving clinical isolates, the study tracks how C. albicans adapts over time in response to antifungal treatment. The results indicate that tolerance mechanisms are more pronounced at 37°C, a temperature reflective of the human body, underscoring the importance of thermal adaptation in the pathogenicity of C. albicans. Additionally, C. albicans clinical isolates exhibit tolerance in both broth and agar plate assays, a phenomenon attributed to a combination of specific genotypic and phenotypic characteristics. Our data support the initial hypothesis that the drug tolerance of C. albicans varies over different time points, reflecting the fungus's adaptive response to fluconazole exposure, particularly as influenced by temperature and subpopulation dynamics.