In News:

A recent study published in PLoS Biology by researchers from Fudan University, China, has uncovered a disturbing link between the agricultural use of a common fungicide and the emergence of azole-resistant Candida tropicalis, a fungal pathogen responsible for high-mortality infections, especially in India and other tropical regions.

Candida tropicalis and Public Health Risk

• Candida tropicalis is a major fungal pathogen, particularly prevalent in India, associated with mortality rates of 55–60%.
• Azole-class antifungal drugs, such as fluconazole and voriconazole, are frontline treatments.
• Growing drug resistance is being reported in clinics globally, raising serious concerns for treatment efficacy and public health.

Fungicide Link to Drug Resistance

• Tebuconazole, a triazole-based fungicide, widely used in agriculture and gardening, has been found to be the primary driver of cross-resistance to clinical azoles in C. tropicalis.
• Tebuconazole accumulates and persists in the environment, exerting selective pressure on fungal strains.
• Clinical strains exposed to tebuconazole showed cross-resistance to both fluconazole and voriconazole.

Mechanism of Resistance: Ploidy Plasticity and Aneuploidy

• Resistant strains exhibit aneuploidy – a deviation in chromosome number, often with duplications or deletions of chromosome segments.
• This phenomenon, termed ploidy plasticity, is rare in most organisms due to its detrimental effects, but in C. tropicalis, it enables adaptive resistance.

Genetic Changes Observed:

• Duplication of TAC1 gene segment led to overexpression of ABC-transporters, proteins that pump out azoles and reduce their effectiveness.
• Deletion of HMG1 gene segment increased the synthesis of ergosterol, a compound crucial to fungal membranes, thus enhancing azole resistance.
• These adaptations allowed the resistant strains to trade growth rate for survival under antifungal pressure.

Emergence of Stable Haploid Strains

• The study unexpectedly identified haploid strains of C. tropicalis among resistant isolates.
• These haploids were found to be mating-competent, raising concerns over the genetic transfer of resistance traits.
• Further genomic analysis confirmed that naturally occurring haploid strains also exist, such as two clinical isolates from Spain.

Virulence and Resistance in Animal Models

• In mouse models, strains with altered ploidy exhibited greater virulence than their progenitor strains when treated with fluconazole.
• This finding suggests a dual threat: enhanced resistance and increased disease severity.

Implications and Concerns

• The unregulated and widespread use of triazole fungicides like tebuconazole in agriculture is unintentionally selecting for clinically significant drug resistance.
• These resistant fungal strains pose a direct threat to human health, particularly in immunocompromised patients and in settings with limited alternative antifungal therapies.
• Resistant strains can potentially spread and recombine through mating, complicating containment efforts.