Osh2 mediates <i>Candida</i> species resistance to miltefosine by regulating zymosterol accumulation
Bibliographic record
Abstract
ABSTRACT Invasive candidiasis poses a growing threat to global public health, compounded by the scarcity of effective antifungal treatments. Miltefosine exhibits broad-spectrum antifungal activity, yet its mechanisms of antifungal action and the development of resistance remain poorly understood. Here, we first generated miltefosine-resistant strains of Candida glabrata through stepwise exposure to increasing drug concentrations. Whole-genome sequencing revealed that nonsense mutations in the OSH2 gene (193C > T and 3177C > A) were key drivers of resistance. Functional validation in Candida albicans confirmed that these OSH2 mutations conferred miltefosine resistance, demonstrating the conserved role of Osh2 across species. Multi-omics profiling of the osh2Δ/Δ mutant revealed significant upregulation of ergosterol biosynthesis genes, including ERG6 and ERG11 , and the accumulation of zymosterol, an intermediate in the ergosterol pathway. Chemogenetic dissection further elucidated the role of sterol metabolism in resistance: erg11Δ/Δ mutants, which are unable to synthesize zymosterol, exhibited hypersusceptibility to miltefosine, whereas erg6Δ/Δ strains, which accumulate zymosterol, showed innate resistance. Exogenous supplementation of zymosterol dose dependently increased the minimum inhibitory concentration of miltefosine in C. albicans and C. glabrata , confirming that zymosterol accumulation is a key determinant of resistance. Our findings establish Osh2 as a critical regulator of membrane sterol flux and demonstrate that fungal lipid metabolic plasticity enables evasion of membrane-targeting antifungals. Therapeutic targeting of zymosterol biosynthesis enzymes may overcome such adaptive resistance mechanisms in invasive candidiasis, providing a new strategy to combat drug-resistant fungal infections.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".