Candida tropicalis Drug Resistance: The Role of Agricultural Fungicide

Overview:

• Candida tropicalis is a major fungal pathogen in India and globally.

• It causes life-threatening infections with a mortality rate of 55–60%.

• Common antifungal treatments include azoles such as fluconazole and voriconazole.

• However, increasing drug resistance is being observed in clinical strains of C. tropicalis.

 Key Finding: Role of Tebuconazole

• A recent study in PLoS Biology by researchers from Fudan University, Shanghai links azole resistance to widespread agricultural use of tebuconazole, an azole-related fungicide.

• Tebuconazole is used in farming and gardening, and can accumulate in the environment.

• Exposure to this fungicide is driving the evolution of C. tropicalis strains resistant to medical azoles.

Mechanism of Resistance: Ploidy Plasticity and Aneuploidy

1. Ploidy Explained:

• Normal organisms, including C. tropicalis, are diploid (2 sets of chromosomes).

• Aneuploidy refers to cells with abnormal chromosome numbers (extra or missing chromosomes).

• In humans, aneuploidy causes disorders like Down Syndrome and usually leads to prenatal death for other chromosomes.

2. C. tropicalis Resistance via Aneuploidy:

• Researchers exposed five tebuconazole-sensitive strains to increasing doses of tebuconazole.

• 35 resistant colonies were isolated, all of which showed:

  • Cross-resistance to fluconazole and voriconazole

  • Altered ploidy, ranging from haploid to triploid

  • Some diploid-looking strains were actually segmental aneuploids

 Genetic Adaptations Observed:

Segmental Duplications:

• Duplicated segments carried resistance-linked genes, especially:

  • TAC1 gene → overexpression increases ABC-transporter, which pumps out azole drugs from the cell.

Segmental Deletions (Haploidisation):

• Deletion of segments containing the HMG1 gene:

  • Lower HMG1 expression boosts ergosterol production

  • Ergosterol is crucial for fungal cell membranes and influences azole susceptibility

  • Less HMG1 → more ergosterol → higher azole resistance

Trade-off Observed:

• Resistant strains grow slower in the absence of drugs, but grow better under drug pressure.

• Genomic imbalance sacrifices growth for increased survival under antifungal stress.

 Discovery of Haploid Strains: A Genetic Breakthrough

• Study unexpectedly discovered stable haploid strains of C. tropicalis.

  • These can mate, offering potential for genetic exchange of resistance traits.

• Researchers confirmed that 2 out of 868 globally recorded strains (from Spain) were naturally haploid.

 Virulence in Animal Models:

• Mouse experiments showed that resistant strains with altered ploidy were:

  • More virulent than progenitor strains

  • Particularly lethal even under fluconazole treatment

 Key Implications & Conclusion:

• Overuse of azole fungicides in agriculture, like tebuconazole, is driving medical antifungal resistance.

• These resistant strains:

  • Show chromosomal alterations (aneuploidy and haploidy)

  • Are cross-resistant to clinical azoles

  • Are potentially more virulent

  • Can mate and spread resistance traits

 Public Health Concern:

• Highlights the link between environmental practices and clinical health outcomes.

• Urges regulation of triazole fungicide use to prevent emergence of multi-drug-resistant fungal pathogens.

 For UPSC (GS-III) Relevance: