ArticleNature communications2024
A secondary mechanism of action for triazole antifungals in Aspergillus fumigatus mediated by hmg1.
Article in Nature communications, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 31 papers.
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Who cites it
31 citing papers in PubMed, 38 citations in OpenAlex.
- Lanosterol synthase inhibition as a potential approach for re-sensitizing triazole-resistantmBio · 2026Article
- Rational design, synthesis, and antimicrobial evaluation of novel 1,2,3-triazole hybrids: structure-activity relationships, molecular docking, and DFT studies.Scientific reports · 2026Article
- Biocontrol mechanisms of a karstic cave-derived Streptomyces sp. GCAL-9 bioactive extract against Colletotrichum musae: insights into ergosterol pathway involvement and metabolomic profiling.Archives of microbiology · 2026Article
- A long noncoding RNA regulates in vitro and in vivo triazole antifungal susceptibility in Aspergillus fumigatus.Genetics · 2026Article
- Engineered pectin-coated copper oxide nanocarriers for controlled fungicide release: a mechanistic exploration of fungal pectinase-mediated delivery and its role in advancing sustainable agriculture.World journal of microbiology & biotechnology · 2026Article
- Rho2-dependent cell wall remodeling boosts the fungistatic activity of manogepix againstCell surface (Amsterdam, Netherlands) · 2026Article
- Thermal adaptation crosstalk with azole response through lncRNA inbioRxiv : the preprint server for biology · 2026Article
- Genotype-Phenotype Relationships in Azole-ResistantJournal of fungi (Basel, Switzerland) · 2026Review
- Prevalence of cyp51A variants in a US collection of Aspergillus fumigatus clinical isolates and comparative analysis of their contribution to triazole antifungal resistance.The Journal of antimicrobial chemotherapy · 2026Article
- Directed evolution of the pathogenic moldAntimicrobial agents and chemotherapy · 2026Article
- Emerging Applications of Triazole Antifungal Drugs.International journal of molecular sciences · 2026Review
- Understanding multi-azole resistance inFrontiers in fungal biology · 2026Article
- Acquired amphotericin B resistance attributed to a mutatedAntimicrobial agents and chemotherapy · 2025Article
- Targeted regulation of sterol biosynthesis genes according to perturbations in ergosterol biosynthesis in fungi.Journal of advanced research · 2025Article
- Evaluation of the efficacy of combination therapy in the treatment of fungal otitis externa.Scientific reports · 2025Article
- A long non-coding RNA regulates triazole antifungal susceptibility and virulence inbioRxiv : the preprint server for biology · 2025Article
- Article
- A correlation study on triglyceride-glucose index and extensive neovascularization within carotid artery plaques.Diabetology & metabolic syndrome · 2025Article
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- Genetic analysis of common triazole resistance mechanisms in a collection ofAntimicrobial agents and chemotherapy · 2025Article
Corrections and comments
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Authors and funding
17 authors at 6 institutions in 2 countries.
Funding
Abstract
Triazole antifungals function as ergosterol biosynthesis inhibitors and are frontline therapy for invasive fungal infections, such as invasive aspergillosis. The primary mechanism of action of triazoles is through the specific inhibition of a cytochrome P450 14-α-sterol demethylase enzyme, Cyp51A/B, resulting in depletion of cellular ergosterol. Here, we uncover a clinically relevant secondary mechanism of action for triazoles within the ergosterol biosynthesis pathway. We provide evidence that triazole-mediated inhibition of Cyp51A/B activity generates sterol intermediate perturbations that are likely decoded by the sterol sensing functions of HMG-CoA reductase and Insulin-Induced Gene orthologs as increased pathway activity. This, in turn, results in negative feedback regulation of HMG-CoA reductase, the rate-limiting step of sterol biosynthesis. We also provide evidence that HMG-CoA reductase sterol sensing domain mutations previously identified as generating resistance in clinical isolates of Aspergillus fumigatus partially disrupt this triazole-induced feedback. Therefore, our data point to a secondary mechanism of action for the triazoles: induction of HMG-CoA reductase negative feedback for downregulation of ergosterol biosynthesis pathway activity. Abrogation of this feedback through acquired mutations in the HMG-CoA reductase sterol sensing domain diminishes triazole antifungal activity against fungal pathogens and underpins HMG-CoA reductase-mediated resistance.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.