{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T15:12:54Z","timestamp":1789398774122,"version":"build-2803163510"},"reference-count":52,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,5,12]],"date-time":"2026-05-12T00:00:00Z","timestamp":1778544000000},"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. Cell. Infect. Microbiol."],"abstract":"<jats:p>\n                    The rising incidence of antifungal resistance in\n                    <jats:italic>Candida<\/jats:italic>\n                    species and emerging non-albicans yeasts has markedly reduced the efficacy of azole antifungal therapy, highlighting the need for resistance modifying strategies. Natural products represent a valuable reservoir of bioactive scaffolds, and computational prioritization facilitates the systematic identification of pharmacologically relevant lead molecules. In this study, we employed an integrated\n                    <jats:italic>in silico-in vitro<\/jats:italic>\n                    antimicrobial pharmacology approach to identify Isosilybin A as a potential ERG1-targeting antifungal adjuvant and to assess its biological relevance using Isosilybin A enriched plant extract. A comprehensive virtual screening of 17,967 phytochemicals from the Indian Medicinal Plants, Phytochemistry And Therapeutics (IMPPAT) database was performed against an AlphaFold-predicted structure of squalene epoxidase (ERG1) from\n                    <jats:italic>Candida albicans<\/jats:italic>\n                    , followed by drug-likeness and ADMET profiling. Seven shortlisted phytochemicals were subjected to 100 ns molecular dynamics simulations. Among these, Isosilybin A demonstrated persistent interactions with key active-site residues of ERG1 and exhibited stable dynamic behavior throughout the simulation. Favorable binding free energy estimated using Molecular Mechanics\/Poisson-Boltzmann Surface Area (MM\/PBSA) method positioning it as the foremost mechanistically prioritized candidate. To experimentally validate this computational prioritization, Isosilybin A enriched\n                    <jats:italic>Silybum marianum<\/jats:italic>\n                    extract was evaluated against azole-resistant\n                    <jats:italic>Candida<\/jats:italic>\n                    species and emerging multidrug-resistant yeast isolates. While the extract alone exhibited no detectable antifungal activity, its combination with fluconazole consistently restored azole susceptibility across all tested isolates. Growth inhibition was observed at a minimum inhibitory concentration of 0.78 mg\/mL extract combined with 0.78 \u03bcg\/mL fluconazole, whereas fluconazole monotherapy remained ineffective. Collectively, these findings establish Isosilybin A as a computationally identified ERG1-interacting antifungal adjuvant, with extract-based\n                    <jats:italic>in vitro<\/jats:italic>\n                    validation supporting its role in restoring fluconazole efficacy against resistant\n                    <jats:italic>Candida<\/jats:italic>\n                    and emerging yeasts. Further studies employing purified compounds are warranted to conclusively delineate the pharmacological contribution of Isosilybin A.\n                  <\/jats:p>","DOI":"10.3389\/fcimb.2026.1774455","type":"journal-article","created":{"date-parts":[[2026,5,12]],"date-time":"2026-05-12T05:46:21Z","timestamp":1778564781000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["In silico identification of isosilybin a targeting squalene epoxidase as an antifungal adjuvant with in vitro validation against azole-resistant Candida and emerging yeasts"],"prefix":"10.3389","volume":"16","author":[{"given":"Akshay Kisan","family":"Mundhe","sequence":"first","affiliation":[{"name":"Department of Integrative Biology, School of Bio Sciences and Technology, Vellore Institute of Technology","place":["Vellore, Tamil Nadu, India"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Reena","family":"Rajkumari","sequence":"additional","affiliation":[{"name":"Department of Integrative Biology, School of Bio Sciences and Technology, Vellore Institute of Technology","place":["Vellore, Tamil Nadu, India"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,5,12]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.47852\/bonviewmedin52025350","article-title":"Repurposing phytocompounds as JAK1 inhibitors for targeting pancreatic cancer: A molecular docking, ADMET, and MD simulation study","author":"Abbas","year":"2025","journal-title":"Medinformatics"},{"key":"B2","first-page":"214","article-title":"South asian epidemic of antifungal therapeutic failures: Congress proceedings and take-home messages","volume-title":"Indian dermatology online journal","author":"Aggarwal","year":"2019"},{"key":"B3","doi-asserted-by":"crossref","DOI":"10.1007\/978-3-030-16807-0","volume-title":"Handbook of 200 medicinal plants: A comprehensive review of their traditional medical uses and scientific justifications","author":"Akbar","year":"2020"},{"key":"B4","doi-asserted-by":"publisher","first-page":"55","DOI":"10.1186\/s12879-019-4710-z","article-title":"Antifungal resistance in patients with candidaemia: A retrospective cohort study","volume":"20","author":"Aldardeer","year":"2020","journal-title":"BMC Infect. 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