{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T16:34:29Z","timestamp":1790354069031,"version":"4.1.0"},"reference-count":26,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,10,21]],"date-time":"2025-10-21T00:00:00Z","timestamp":1761004800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Microbiol."],"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p><jats:italic>Candida glabrata<\/jats:italic> is an opportunistic fungal pathogen known for its ability to rapidly develop resistance to antifungal agents. Tunicamycin (TUN), an inhibitor of N-linked glycosylation, induces Endoplasmic Reticulum (ER) stress, but the adaptive mechanisms enabling <jats:italic>C. glabrata<\/jats:italic> to survive TUN exposure remain poorly understood.<\/jats:p><\/jats:sec><jats:sec><jats:title>Objective<\/jats:title><jats:p>This study aimed to identify and characterize the genetic and phenotypic adaptations that confer TUN resistance in <jats:italic>C. glabrata<\/jats:italic> and evaluate their stability in the absence of drug pressure.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We exposed <jats:italic>C. glabrata<\/jats:italic> strain BG2 to sub-inhibitory (0.5 \u03bcg\/mL) and inhibitory (1\u20138 \u03bcg\/mL) TUN concentrations and isolated resistant mutants. Phenotypic characterization included growth assays, mitochondrial function tests (YPG medium), and fluconazole (FLC) susceptibility testing. Whole-genome sequencing assessed chromosomal alterations, and serial passaging in drug-free medium evaluated adaptation stability.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Under TUN stress, <jats:italic>C. glabrata<\/jats:italic> adopted two distinct resistance strategies: (1) mitochondrial dysfunction (petite formation), which conferred cross-resistance to FLC, and (2) aneuploidy, particularly disomy of chromosome C (ChrCx2), often accompanied by additional chromosomal gains in high-TUN conditions. However, both adaptations exhibited significant trade-offs: petite mutants retained irreversible respiratory deficiency but lost TUN and FLC resistance upon passaging, while aneuploid strains rapidly reverted to euploidy in non-selective conditions, abolishing TUN resistance.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p><jats:italic>C. glabrata<\/jats:italic> survives TUN stress through unstable genetic adaptations\u2014petite formation and aneuploidy\u2014that are rapidly selected against in drug-free environments. These findings highlight the evolutionary constraints of antifungal resistance mechanisms and suggest that intermittent therapy may help counteract resistance development.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fmicb.2025.1675175","type":"journal-article","created":{"date-parts":[[2025,10,21]],"date-time":"2025-10-21T05:37:34Z","timestamp":1761025054000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":2,"title":["Dual adaptive strategies in Candida glabrata under tunicamycin stress: petite mutations and chromosome C aneuploidy drive transient drug resistance"],"prefix":"10.3389","volume":"16","author":[{"given":"Yubo","family":"Dong","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chunhua","family":"Ma","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuai","family":"Bai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chen","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,10,21]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"100","DOI":"10.1186\/s13073-014-0100-8","article-title":"YMAP: a pipeline for visualization of copy number variation and loss of heterozygosity in eukaryotic pathogens","volume":"6","author":"Abbey","year":"2014","journal-title":"Genome Med."},{"key":"B2","doi-asserted-by":"publisher","first-page":"myae041","DOI":"10.1093\/mmy\/myae041","article-title":"Candida glabrata (Nakaseomyces glabrata): a systematic review of clinical and microbiological data from 2011 to 2021 to inform the World Health Organization fungal priority pathogens list","volume":"62","author":"Beardsley","year":"2024","journal-title":"Med. 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