{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,6,24]],"date-time":"2026-06-24T05:48:10Z","timestamp":1782280090772,"version":"3.54.5"},"posted":{"date-parts":[[2025,2,21]]},"group-title":"Microbiology","reference-count":71,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,2,21]],"date-time":"2025-02-21T00:00:00Z","timestamp":1740096000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,2,19]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Through screening a comprehensive collection of drugs approved for human use, we identified over 20 that oppose the antifungal activity of the echinocandins upon the infectious yeast,\n                  <jats:italic>Candida albicans<\/jats:italic>\n                  . More detailed evaluation of five such drugs, including the atypical antipsychotic aripiprazole and the tyrosine kinase inhibitor ponatinib, indicated they promote\n                  <jats:italic>C. albicans<\/jats:italic>\n                  survival following exposure to the echinocandin antifungals. The activity of the five selected antagonists was dependent upon the Mkc1p MAPK pathway, however, ponatinib was paradoxically shown to suppress phosphorylation and therefore activation of Mkc1p itself. Components of several other signaling pathways are also required, including those of calcineurin and casein kinase-2, suggesting the observed antagonism required much of the cell wall stress responses previously described for\n                  <jats:italic>C. albicans<\/jats:italic>\n                  . Transcriptome analysis revealed that the antagonists stimulated the expression of genes involved in xenobiotic and antifungal resistance, and suppressed the expression of genes associated with hyphal growth. Thus, the echinocandin antagonistic drugs modulate\n                  <jats:italic>C. albicans<\/jats:italic>\n                  physiology in ways that could impact its pathogenicity and\/or response to therapeutic intervention. Finally, a mutant lacking the Efg1p transcription factor, which has a central role in the activation of\n                  <jats:italic>C. albicans<\/jats:italic>\n                  hyphal growth was found to have intrinsically high levels of echinocandin tolerance, suggesting a link between modulation of morphogenesis related signaling and echinocandin tolerance.\n                <\/jats:p>\n                <jats:sec>\n                  <jats:title>Importance<\/jats:title>\n                  <jats:p>\n                    We report a substantial number of previously unknown drug interactions that modulate the echinocandin sensitivity of one of the most prevalent human fungal pathogens,\n                    <jats:italic>Candida albicans<\/jats:italic>\n                    . The echinocandins are the first line therapy for treating disseminated and often lethal\n                    <jats:italic>Candida<\/jats:italic>\n                    infections, that account for &gt;75% of invasive fungal infections in the U.S.. For largely unknown reasons, a substantial number of patients with invasive candidiasis fail to respond to treatment with these drugs. The finding of this study suggest that co-administered medications have the potential to influence the therapeutic outcomes of invasive fungal infections through modulating antifungal drug tolerance and\/or fungal pathogenicity. The potential for echinocandin antagonistic medications to influence therapeutic outcomes is discussed.\n                  <\/jats:p>\n                <\/jats:sec>","DOI":"10.1101\/2025.02.18.638903","type":"posted-content","created":{"date-parts":[[2025,2,21]],"date-time":"2025-02-21T09:41:18Z","timestamp":1740130878000},"source":"Crossref","is-referenced-by-count":0,"title":["A screen to identify antifungal antagonists reveals a variety of pharmacotherapies induce echinocandin tolerance in\n                  <i>Candida albicans<\/i>"],"prefix":"10.64898","author":[{"given":"Parker","family":"Reitler","sequence":"first","affiliation":[{"name":"Department of Clinical Pharmacy and Translational Science, College of Pharmacy, University of Tennessee Health Sciences Center, Memphis, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9733-9152","authenticated-orcid":false,"given":"Christian A.","family":"DeJarnette","sequence":"additional","affiliation":[{"name":"Department of Clinical Pharmacy and Translational Science, College of Pharmacy, University of Tennessee Health Sciences Center, Memphis, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ravinder","family":"Kumar","sequence":"additional","affiliation":[{"name":"Department of Clinical Pharmacy and Translational Science, College of Pharmacy, University of Tennessee Health Sciences Center, Memphis, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katie M.","family":"Tucker","sequence":"additional","affiliation":[{"name":"Department of Clinical Pharmacy and Translational Science, College of Pharmacy, University of Tennessee Health Sciences Center, Memphis, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tracy L.","family":"Peters","sequence":"additional","affiliation":[{"name":"Department of Pharmacy and Pharmaceutical Sciences, St Jude Children\u2019s Research Hospital, Memphis, TN, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nathaniel R","family":"Twarog","sequence":"additional","affiliation":[{"name":"Department of Chemical Biology and Therapeutics, St Jude Children\u2019s Research Hospital, Memphis, TN, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6266-2910","authenticated-orcid":false,"given":"Anang A.","family":"Shelat","sequence":"additional","affiliation":[{"name":"Department of Chemical Biology and Therapeutics, St Jude Children\u2019s Research Hospital, Memphis, TN, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4083-3130","authenticated-orcid":false,"given":"Glen E.","family":"Palmer","sequence":"additional","affiliation":[{"name":"Department of Clinical Pharmacy and Translational Science, College of Pharmacy, University of Tennessee Health Sciences Center, Memphis, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026041110463609000_2025.02.18.638903v1.1","doi-asserted-by":"publisher","DOI":"10.1093\/cid\/ciy776"},{"key":"2026041110463609000_2025.02.18.638903v1.2","doi-asserted-by":"publisher","DOI":"10.1086\/599039"},{"key":"2026041110463609000_2025.02.18.638903v1.3","doi-asserted-by":"publisher","DOI":"10.1093\/clinids\/20.6.1526"},{"key":"2026041110463609000_2025.02.18.638903v1.4","doi-asserted-by":"publisher","DOI":"10.1001\/archinte.1995.00430110089009"},{"key":"2026041110463609000_2025.02.18.638903v1.5","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.3004404"},{"key":"2026041110463609000_2025.02.18.638903v1.6","doi-asserted-by":"publisher","DOI":"10.1086\/520192"},{"key":"2026041110463609000_2025.02.18.638903v1.7","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(07)60917-9"},{"key":"2026041110463609000_2025.02.18.638903v1.8","doi-asserted-by":"publisher","DOI":"10.2165\/11585270-000000000-00000"},{"key":"2026041110463609000_2025.02.18.638903v1.9","doi-asserted-by":"publisher","DOI":"10.1086\/598933"},{"key":"2026041110463609000_2025.02.18.638903v1.10","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa021585"},{"key":"2026041110463609000_2025.02.18.638903v1.11","doi-asserted-by":"publisher","DOI":"10.1086\/520980"},{"key":"2026041110463609000_2025.02.18.638903v1.12","doi-asserted-by":"publisher","DOI":"10.1093\/cid\/ciy827"},{"key":"2026041110463609000_2025.02.18.638903v1.13","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa040446"},{"key":"2026041110463609000_2025.02.18.638903v1.14","doi-asserted-by":"publisher","DOI":"10.1016\/j.amjmed.2011.11.001"},{"key":"2026041110463609000_2025.02.18.638903v1.15","doi-asserted-by":"publisher","DOI":"10.1016\/S1473-3099(02)00181-0"},{"key":"2026041110463609000_2025.02.18.638903v1.16","unstructured":"Rex, J.H. , Reference method for broth dilution antifungal susceptibility testing of filamentous fungi: approved standard. (No Title), 2008."},{"key":"2026041110463609000_2025.02.18.638903v1.17","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.00116-08"},{"key":"2026041110463609000_2025.02.18.638903v1.18","doi-asserted-by":"publisher","DOI":"10.1128\/JCM.01901-07"},{"key":"2026041110463609000_2025.02.18.638903v1.19","doi-asserted-by":"publisher","DOI":"10.1128\/JCM.44.3.760-763.2006"},{"key":"2026041110463609000_2025.02.18.638903v1.20","doi-asserted-by":"publisher","DOI":"10.1086\/504810"},{"key":"2026041110463609000_2025.02.18.638903v1.21","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.48.12.4911-4914.2004"},{"key":"2026041110463609000_2025.02.18.638903v1.22","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.33.2.147"},{"key":"2026041110463609000_2025.02.18.638903v1.23","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2015.10.018"},{"key":"2026041110463609000_2025.02.18.638903v1.24","doi-asserted-by":"publisher","DOI":"10.1080\/21505594.2015.1039885"},{"key":"2026041110463609000_2025.02.18.638903v1.25","doi-asserted-by":"publisher","DOI":"10.1038\/msb.2011.31"},{"key":"2026041110463609000_2025.02.18.638903v1.26","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0609370104"},{"key":"2026041110463609000_2025.02.18.638903v1.27","doi-asserted-by":"crossref","unstructured":"Butts, A. , et al., Commonly Used Oncology Drugs Decrease Antifungal Effectiveness against Candida and Aspergillus Species. Antimicrob Agents Chemother, 2018. 62(7).","DOI":"10.1128\/AAC.00504-18"},{"key":"2026041110463609000_2025.02.18.638903v1.28","doi-asserted-by":"crossref","unstructured":"Butts, A. , et al., A Systematic Screen Reveals a Diverse Collection of Medications That Induce Antifungal Resistance in Candida Species. Antimicrob Agents Chemother, 2019. 63(5).","DOI":"10.1128\/AAC.00054-19"},{"key":"2026041110463609000_2025.02.18.638903v1.29","doi-asserted-by":"publisher","DOI":"10.1128\/mbio.01249-24"},{"key":"2026041110463609000_2025.02.18.638903v1.30","doi-asserted-by":"publisher","DOI":"10.1177\/02537176211046525"},{"key":"2026041110463609000_2025.02.18.638903v1.31","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.01034-16"},{"key":"2026041110463609000_2025.02.18.638903v1.32","doi-asserted-by":"crossref","unstructured":"Butts, A. , et al., Target Abundance-Based Fitness Screening (TAFiS) Facilitates Rapid Identification of Target-Specific and Physiologically Active Chemical Probes. mSphere, 2017. 2(5).","DOI":"10.1128\/mSphere.00379-17"},{"key":"2026041110463609000_2025.02.18.638903v1.33","doi-asserted-by":"crossref","unstructured":"Johnson, D.L. , et al., Ccr4-Not ubiquitin ligase signaling regulates ribosomal protein homeostasis and inhibits 40S ribosomal autophagy. bioRxiv, 2023.","DOI":"10.1101\/2023.08.28.555095"},{"key":"2026041110463609000_2025.02.18.638903v1.34","doi-asserted-by":"publisher","DOI":"10.1128\/iai.00072-24"},{"key":"2026041110463609000_2025.02.18.638903v1.35","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.48.9.3407-3411.2004"},{"key":"2026041110463609000_2025.02.18.638903v1.36","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.00999-09"},{"key":"2026041110463609000_2025.02.18.638903v1.37","doi-asserted-by":"publisher","DOI":"10.1093\/infdis\/137.2.122"},{"key":"2026041110463609000_2025.02.18.638903v1.38","doi-asserted-by":"publisher","DOI":"10.1111\/j.1744-7348.1939.tb06990.x"},{"key":"2026041110463609000_2025.02.18.638903v1.39","doi-asserted-by":"publisher","DOI":"10.1111\/j.1601-0825.1997.tb00336.x"},{"key":"2026041110463609000_2025.02.18.638903v1.40","doi-asserted-by":"publisher","DOI":"10.1021\/acs.bioconjchem.6b00112"},{"key":"2026041110463609000_2025.02.18.638903v1.41","doi-asserted-by":"publisher","DOI":"10.1091\/mbc.E07-06-0581"},{"key":"2026041110463609000_2025.02.18.638903v1.42","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0407097102"},{"key":"2026041110463609000_2025.02.18.638903v1.43","doi-asserted-by":"publisher","DOI":"10.1128\/mBio.00986-15"},{"key":"2026041110463609000_2025.02.18.638903v1.44","doi-asserted-by":"publisher","DOI":"10.1038\/nature17625"},{"key":"2026041110463609000_2025.02.18.638903v1.45","doi-asserted-by":"publisher","DOI":"10.1128\/EC.00279-10"},{"key":"2026041110463609000_2025.02.18.638903v1.46","doi-asserted-by":"publisher","DOI":"10.1128\/EC.00194-06"},{"key":"2026041110463609000_2025.02.18.638903v1.47","doi-asserted-by":"publisher","DOI":"10.1091\/mbc.E07-11-1110"},{"key":"2026041110463609000_2025.02.18.638903v1.48","doi-asserted-by":"crossref","unstructured":"Yadav, A. , S.K. Sah , D.S. Perlin , and E. Rustchenko , Candida albicans Genes Modulating Echinocandin Susceptibility of Caspofungin-Adapted Mutants Are Constitutively Expressed in Clinical Isolates with Intermediate or Full Resistance to Echinocandins. J Fungi (Basel), 2024. 10(3).","DOI":"10.3390\/jof10030224"},{"key":"2026041110463609000_2025.02.18.638903v1.49","doi-asserted-by":"publisher","DOI":"10.1111\/mmi.14148"},{"key":"2026041110463609000_2025.02.18.638903v1.50","doi-asserted-by":"publisher","DOI":"10.3389\/fcimb.2022.855229"},{"key":"2026041110463609000_2025.02.18.638903v1.51","doi-asserted-by":"crossref","unstructured":"Kornitzer, D ., Regulation of Candida albicans Hyphal Morphogenesis by Endogenous Signals. J Fungi (Basel), 2019. 5(1).","DOI":"10.3390\/jof5010021"},{"key":"2026041110463609000_2025.02.18.638903v1.52","doi-asserted-by":"publisher","DOI":"10.1091\/mbc.E04-02-0144"},{"key":"2026041110463609000_2025.02.18.638903v1.53","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.00095-07"},{"key":"2026041110463609000_2025.02.18.638903v1.54","doi-asserted-by":"publisher","DOI":"10.1038\/nrmicro2711"},{"key":"2026041110463609000_2025.02.18.638903v1.55","doi-asserted-by":"crossref","unstructured":"Ibe, C. and C.A. Munro , Fungal Cell Wall Proteins and Signaling Pathways Form a Cytoprotective Network to Combat Stresses. J Fungi (Basel), 2021. 7(9).","DOI":"10.3390\/jof7090739"},{"key":"2026041110463609000_2025.02.18.638903v1.56","doi-asserted-by":"publisher","DOI":"10.1128\/EC.00278-12"},{"key":"2026041110463609000_2025.02.18.638903v1.57","doi-asserted-by":"publisher","DOI":"10.1080\/21505594.2016.1201250"},{"key":"2026041110463609000_2025.02.18.638903v1.58","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2958.2005.05037.x"},{"key":"2026041110463609000_2025.02.18.638903v1.59","doi-asserted-by":"crossref","unstructured":"Liu, Z. and L.C. Myers , Mediator Tail Module Is Required for Tac1-Activated CDR1 Expression and Azole Resistance in Candida albicans. Antimicrob Agents Chemother, 2017. 61(11).","DOI":"10.1128\/AAC.01342-17"},{"key":"2026041110463609000_2025.02.18.638903v1.60","doi-asserted-by":"publisher","DOI":"10.1186\/gb-2004-5-7-230"},{"key":"2026041110463609000_2025.02.18.638903v1.61","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.00527-18"},{"key":"2026041110463609000_2025.02.18.638903v1.62","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.01034-16"},{"key":"2026041110463609000_2025.02.18.638903v1.63","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.41.7.1482"},{"key":"2026041110463609000_2025.02.18.638903v1.64","doi-asserted-by":"publisher","DOI":"10.1186\/sl3104-023-06661-z"},{"key":"2026041110463609000_2025.02.18.638903v1.65","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.01417-13"},{"key":"2026041110463609000_2025.02.18.638903v1.66","doi-asserted-by":"publisher","DOI":"10.1128\/mbio.0007413"},{"key":"2026041110463609000_2025.02.18.638903v1.67","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1009839"},{"key":"2026041110463609000_2025.02.18.638903v1.68","doi-asserted-by":"publisher","DOI":"10.1128\/EC.2.3.422-430.2003"},{"key":"2026041110463609000_2025.02.18.638903v1.69","doi-asserted-by":"publisher","DOI":"10.1093\/emboj\/21.4.546"},{"key":"2026041110463609000_2025.02.18.638903v1.70","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.143.4.935"},{"key":"2026041110463609000_2025.02.18.638903v1.71","doi-asserted-by":"publisher","DOI":"10.1128\/aac.01619-23"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1101\/2025.02.18.638903","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,24]],"date-time":"2026-06-24T04:56:39Z","timestamp":1782276999000},"score":1,"resource":{"primary":{"URL":"http:\/\/biorxiv.org\/lookup\/doi\/10.1101\/2025.02.18.638903"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,2,21]]},"references-count":71,"URL":"https:\/\/doi.org\/10.1101\/2025.02.18.638903","relation":{"is-preprint-of":[{"id-type":"doi","id":"10.1128\/aac.00484-25","asserted-by":"subject"}]},"subject":[],"published":{"date-parts":[[2025,2,21]]},"subtype":"preprint"}}