Parallel evolution of fluconazole resistance and tolerance in .

INTRODUCTION

With the growing population of immunocompromised individuals, opportunistic fungal pathogens pose a global health threat. species, particularly and non-albicans species such as , are the most prevalent pathogenic fungi. Azoles, especially fluconazole, are widely used therapeutic options.

OBJECTIVE

This study investigates how adapts to fluconazole, with a focus on understanding the factors regulating fluconazole tolerance and its relationship to resistance.

METHODS

This study compared the factors regulating fluconazole tolerance between and . We analyzed the impact of temperature on fluconazole tolerance, and requirement of calcineurin and Hsp90 for maintenance of fluconazole tolerance. We isolated colonies from edge, inside and outside of inhibition zone in disk diffusion assays. And we exposed strain to high concentrations of fluconazole and investigated the mutants for development of fluconazole resistance and tolerance.

RESULTS

We found temperature modulated tolerance in the opposite way in strain YJB-T1891 and strain CG4. Calcineurin and Hsp90 were required for maintenance of fluconazole tolerance in both species. Colonies from inside and outside of inhibition zones did not exhibited mutated phenotype, but colonies isolated from edge of inhibition zone exhibited diverse phenotype changes. Moreover, we discovered that high concentrations (16-128 μg/mL) of fluconazole induce the simultaneous but parallel development of tolerance and resistance in , unlike the sole development of tolerance in .

CONCLUSION

This study highlights that while tolerance to fluconazole is a common response in species, the specific molecular mechanisms and evolutionary pathways that lead to this response vary between species. Our findings emphasize the importance of understanding the regulation of fluconazole tolerance in different species to develop effective therapeutic strategies.