Browsing by Author "Albehaijani, Samah Hamad I"

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Defining the Genetic Causes of Antifungal Drug Resistance in Cryptococcus neoformans
(Royal Melbourne Institute of Technology RMIT, 2024) Albehaijani, Samah Hamad I; Assoc Huynh, Tien; Boyce, Kylie
Immunocompromised individuals face heightened morbidity and mortality from fungal infections, contributing to 1.5 million annual deaths globally. Cryptococcus neoformans, an encapsulated yeast, is a major cause of life-threatening meningoencephalitis and meningitis, typically treated with fluconazole (FLC). However, widespread FLC use in clinics and agriculture has driven the evolution of resistant strains, compromising treatment efficacy. The World Health Organization (WHO) recognises C. neoformans as a critical public health threat, highlighting azole resistance as a primary concern due to its frequent use in long-term monotherapy. While the microevolution of azole resistance in C. neoformans has been studied, the underlying genetic mechanisms remain poorly understood. This research aimed to elucidate the microevolution of FLC resistance in C. neoformans through genetic determinants, measuring the DNA content, chromosomal changes, and cell morphological changes before, and after fluconazole treatment. Our findings demonstrated that FLC exposure induces whole genome amplification rather than specific chromosome amplification. We also observed that FLC resistance can arise independently of ERG11 mutations, the most frequently cited resistance mechanism. Instead, mutations in MSH2 were identified as a common evolutionary route to FLC resistance. We also highlighted the high plasticity of C. neoformans under drug exposure. finally, we revealed some putative metabolic functions associated with antifungal resistance. This study represents the first comprehensive characterisation of polygenic resistance development through point mutations in Cryptococcus. Consequently, this research provides a foundation for developing targeted genetic therapies to mitigate the emergence of drug-resistant strains.
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