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ORIGINAL RESEARCH article

Front. Microbiol.
Sec. Antimicrobials, Resistance and Chemotherapy
Volume 15 - 2024 | doi: 10.3389/fmicb.2024.1450557

Antifungal Drug Tolerance Mediated by Trisomy of Chromosome R in Candida albicans

Provisionally accepted
Yi Xu Yi Xu 1,2*Lijun Zheng Lijun Zheng 3Chen Wang Chen Wang 2Liangsheng Guo Liangsheng Guo 3
  • 1 Jinan Military General Hospital, Jinan, China
  • 2 960th Hospital of the PLA, Jinan, Shandong Province, China
  • 3 Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu Province, China

The final, formatted version of the article will be published soon.

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

    Keywords: Candida albicans, Ketoconazole, antifungal agent, Drug Tolerance, Chromosomal aneuploidy, Hsp90, Calcineurin

    Received: 20 Jun 2024; Accepted: 18 Jul 2024.

    Copyright: © 2024 Xu, Zheng, Wang and Guo. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

    * Correspondence: Yi Xu, Jinan Military General Hospital, Jinan, China

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