Uncovering the connection between tunicamycin-induced respiratory deficiency and reduced fluconazole tolerance in Candida glabrata

Frontiers in Microbiology, Journal Year: 2025, Volume and Issue: 16

Published: April 28, 2025

Introduction Candida glabrata is a prevalent opportunistic fungal pathogen in humans, and fluconazole (FLC) one of the most commonly used antifungal agents. However, molecular mechanisms underlying FLC tolerance C. remain largely unexplored. Objective This study aims to identify novel regulating tolerance, with particular focus on tunicamycin (TUN)-induced respiratory deficiency. Methods We employed three distinct experimental approaches investigate impact TUN tolerance: (1) co-treatment FLC, (2) exclusive exposure TUN, (3) induction petite formation through alternative methods. Additionally, gene expression analyses were conducted evaluate regulation key genes involved ergosterol biosynthesis pathway. Results Our findings reveal that significantly abolishes , primarily formation, which characterized by mitochondrial dysfunction. Notably, treatment resulted downregulation critical genes, including ERG1 ERG11 indicating metabolic shift response endoplasmic reticulum (ER) stress. Furthermore, both TUN-induced ethidium bromide-induced petites displayed cross-resistance but showed reduced FLC. Conclusion These results underscore pivotal role ER stress modulating via deficiency alterations metabolism. emphasizes importance integrity maintaining drug suggests potential therapeutic strategies targeting pathways associated tolerance. A deeper understanding these may enhance our capacity effectively combat infections.

Language: Английский

Ketoconazole induces reversible antifungal drug tolerance mediated by trisomy of chromosome R in Candida albicans

Frontiers in Microbiology, Journal Year: 2024, Volume and Issue: 15

Published: July 30, 2024

Background The emergence of tolerance to antifungal agents in Candida albicans complicates the treatment fungal infections. Understanding mechanisms underlying this is crucial for developing effective therapeutic strategies. Objective This study aims elucidate genetic and molecular basis ketoconazole C. , focusing on roles chromosomal aneuploidy, Hsp90, calcineurin. Methods wild-type strain SC5314 was exposed increasing concentrations (0.015–32 μg/mL) select tolerant adaptors. Disk diffusion spot assays were used assess tolerance. Whole-genome sequencing identified changes Hsp90 calcineurin maintaining investigated using specific inhibitors knockout strains. Results Adaptors exhibited up 16 μg/mL, a significant increase from parent strain’s inhibition at 0.015 μg/mL. All adaptors showed amplification chromosome R, with 29 having trisomy one tetrasomy. aneuploidy unstable, reverting euploidy losing drug-free conditions. Both essential Inhibition these proteins resulted loss efflux gene CDR1 not required development Chromosome R tetrasomy induce cross-tolerance other azole agents, including clotrimazole miconazole, but classes, such as echinocandins pyrimidines, exemplified by caspofungin 5-flucytosine. Conclusion Ketoconazole mediated specifically amplification, requires These findings highlight potential targets intervention combat improve outcomes.

Language: Английский

Parallel evolution of fluconazole resistance and tolerance in Candida glabrata

Frontiers in Cellular and Infection Microbiology, Journal Year: 2024, Volume and Issue: 14

Published: Sept. 27, 2024

Introduction With the growing population of immunocompromised individuals, opportunistic fungal pathogens pose a global health threat. Candida species, particularly C. albicans and non-albicans species such as glabrata , are most prevalent pathogenic fungi. Azoles, especially fluconazole, widely used therapeutic options. Objective This study investigates how adapts to with focus on understanding factors regulating fluconazole tolerance its relationship resistance. Methods compared between . We analyzed impact temperature tolerance, requirement calcineurin Hsp90 for maintenance tolerance. isolated colonies from edge, inside outside inhibition zone in disk diffusion assays. And we exposed strain high concentrations investigated mutants development resistance Results found modulated opposite way YJB-T1891 CG4. Calcineurin were required both species. Colonies zones did not exhibited mutated phenotype, but edge diverse phenotype changes. Moreover, discovered that (16-128 μg/mL) induce simultaneous parallel unlike sole Conclusion highlights while is common response specific molecular mechanisms evolutionary pathways lead this vary Our findings emphasize importance regulation different develop effective strategies.

Language: Английский