{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,3,17]],"date-time":"2026-03-17T18:00:18Z","timestamp":1773770418155,"version":"3.50.1"},"posted":{"date-parts":[[2025,9,22]]},"group-title":"Molecular Biology","reference-count":21,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,9,22]],"date-time":"2025-09-22T00:00:00Z","timestamp":1758499200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,9,22]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:p>\n                  Fks1 catalyzes the synthesis of \u03b2-1,3-glucans, a major structural component of the fungal cell wall, and is the primary target of the antifungal drug caspofungin. Mutations in Fks1 confer caspofungin resistance by disrupting its interaction with the drug, thereby reducing inhibition of Fks1 enzymatic activity. Previous studies demonstrated that translation of the\n                  <jats:italic>FKS1<\/jats:italic>\n                  mRNA was highly dependent on the translation initiation helicases eIF4A and Ded1 (1). Therefore, we investigated whether treatment of\n                  <jats:italic>Saccharomyces cerevisiae<\/jats:italic>\n                  cells with the eIF4A inhibitor Rocaglamide A (RocA) or mutation of Ded1 affects translation of\n                  <jats:italic>FKS1<\/jats:italic>\n                  and susceptibility to caspofungin. Using WT and temperature-sensitive\n                  <jats:italic>ded1-ts<\/jats:italic>\n                  strains, we demonstrated that RocA enhanced caspofungin-mediated growth inhibition and translation repression. Sensitivity to both drugs was further enhanced in\n                  <jats:italic>ded1-ts<\/jats:italic>\n                  strains, suggesting specifically targeting Ded1 in fungi could be an effective mechanism to prevent caspofungin resistance. We extended the analysis to\n                  <jats:italic>Candida glabrata<\/jats:italic>\n                  , a related fungal pathogen, and found similar results. Importantly, combining RocA with caspofungin was fungicidal in both species, suggesting the combination could decrease development of caspofungin resistance in pathogenic yeasts. Together these findings highlight the potential of targeting translation initiation helicases for effective combination antifungal treatments.\n                <\/jats:p>","DOI":"10.1101\/2025.09.21.677667","type":"posted-content","created":{"date-parts":[[2025,9,23]],"date-time":"2025-09-23T05:10:26Z","timestamp":1758604226000},"source":"Crossref","is-referenced-by-count":1,"title":["Translation Inhibition by Rocaglamide A Enhances Susceptibility of Yeasts to Caspofungin"],"prefix":"10.64898","author":[{"given":"Qian","family":"He","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Peter J.","family":"Schuessler","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Aravind","family":"Srinivasan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jessie","family":"Caprino","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Joseph","family":"Barbi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9983-2485","authenticated-orcid":false,"given":"Sarah E.","family":"Walker","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"key":"2025092602151147000_2025.09.21.677667v1.1","doi-asserted-by":"publisher","DOI":"10.1101\/gr.191601.115"},{"issue":"3","key":"2025092602151147000_2025.09.21.677667v1.2","first-page":"267","article-title":"The Fungal Cell Wall: Structure, Biosynthesis, and Function","volume":"5","year":"2017","journal-title":"Microbiology Spectrum"},{"key":"2025092602151147000_2025.09.21.677667v1.3","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1016\/j.tcsw.2018.09.001","article-title":"Yeast species-specific, differential inhibition of \u03b2-1,3-glucan synthesis by poacic acid and caspofungin","volume":"3","year":"2018","journal-title":"The Cell Surface"},{"key":"2025092602151147000_2025.09.21.677667v1.4","doi-asserted-by":"publisher","DOI":"10.1128\/EC.00082-12"},{"key":"2025092602151147000_2025.09.21.677667v1.5","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.46.8.2462-2469.2002"},{"key":"2025092602151147000_2025.09.21.677667v1.6","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.48.10.3871-3876.2004"},{"key":"2025092602151147000_2025.09.21.677667v1.7","doi-asserted-by":"crossref","unstructured":"Valli\u00e8res C , Raulo R , Dickinson M , Avery SV . Novel Combinations of Agents Targeting Translation That Synergistically Inhibit Fungal Pathogens. Frontiers in Microbiology. 2018;9.","DOI":"10.3389\/fmicb.2018.02355"},{"key":"2025092602151147000_2025.09.21.677667v1.8","doi-asserted-by":"crossref","unstructured":"Fu C , Zhang X , Veri AO , Iyer KR , Lash E , Xue A , et al. Leveraging machine learning essentiality predictions and chemogenomic interactions to identify antifungal targets. Nature Communications. 2021;12(1).","DOI":"10.1038\/s41467-021-26850-3"},{"key":"2025092602151147000_2025.09.21.677667v1.9","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.49.1.52-56.2005"},{"key":"2025092602151147000_2025.09.21.677667v1.10","doi-asserted-by":"crossref","unstructured":"Iyer KR , Whitesell L , Porco JA , Henkel T , Brown LE , Robbins N , et al. Translation Inhibition by Rocaglates Activates a Species-Specific Cell Death Program in the Emerging Fungal Pathogen Candida auris. mBio. 2020;11(2).","DOI":"10.1128\/mBio.03329-19"},{"issue":"4","key":"2025092602151147000_2025.09.21.677667v1.11","doi-asserted-by":"crossref","first-page":"475","DOI":"10.1016\/j.chembiol.2020.11.008","article-title":"Dual targeting of DDX3 and eIF4A by the translation inhibitor rocaglamide A","volume":"28","year":"2021","journal-title":"Cell Chemical Biology"},{"key":"2025092602151147000_2025.09.21.677667v1.12","unstructured":"WHO fungal priority pathogens list to guide research, development and public health action. 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