{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,26]],"date-time":"2026-09-26T00:16:25Z","timestamp":1790381785158,"version":"4.1.0"},"reference-count":47,"publisher":"American Society for Microbiology","issue":"5","license":[{"start":{"date-parts":[[2025,5,14]],"date-time":"2025-05-14T00:00:00Z","timestamp":1747180800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2025,5,14]],"date-time":"2025-05-14T00:00:00Z","timestamp":1747180800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"funder":[{"DOI":"10.13039\/100000060","name":"National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["R21-AI149015"],"award-info":[{"award-number":["R21-AI149015"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["mBio"],"published-print":{"date-parts":[[2025,5,14]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title\/>\n                    <jats:p>\n                      Coccidioidomycosis or valley fever is a treatment-limited fungal infection endemic to the alkaline deserts of North and South America for which two classes of antifungals are typically used: the polyenes and the triazoles. In light of the limited usefulness of the echinocandins and a growing trend of azole resistance, it is essential that we identify novel antifungals. In this study, we have developed and optimized a screening methodology for identifying potential antifungals effective against\n                      <jats:italic toggle=\"yes\">Coccidioides<\/jats:italic>\n                      spherule initials using a metabolic assay, used it to screen four diverse drug libraries with limited drug overlap, and established safety and efficacy data for a majority of the compounds, including the Broad Repurposing Hub, Prestwick Chemicals 1520, Selleck L8200 Anti-parasitic, and MedChemExpress CNS Penetrants libraries. Hits were defined as compounds with strong metabolic inhibition (\u226570%), which were significantly different compared to the median plate readout (B-scores \u2264 \u22123). We identified 30 promising hits and found 12 compounds exhibiting half-maximal inhibitory concentrations below 6 \u00b5M. Among these, oxethazaine, niclosamide ethanolamine, 10058-F4, niclosamide (NIC), and pentamidine isethionate showed synergy with amphotericin B, suggesting their potential use in combination therapy. Further assessment of lead compounds\u2019 effects on spherules was conducted by image flow cytometry. Additionally, we explored the potential to use an attenuated, Biosafety Level 2 containment mutant,\n                      <jats:italic toggle=\"yes\">C. posadasii<\/jats:italic>\n                      \u2206\n                      <jats:italic toggle=\"yes\">cts2<\/jats:italic>\n                      \/\u2206\n                      <jats:italic toggle=\"yes\">ard1<\/jats:italic>\n                      \/\u2206\n                      <jats:italic toggle=\"yes\">cts3<\/jats:italic>\n                      (\u2206T), as a surrogate model for drug screening. Overall, our findings provide a foundation for future research focused on screening and developing novel coccidioidomycosis treatments.\n                    <\/jats:p>\n                    <jats:sec>\n                      <jats:title>IMPORTANCE<\/jats:title>\n                      <jats:p>\n                        The antifungal treatment arsenal is especially limited against\n                        <jats:italic toggle=\"yes\">Coccidioides<\/jats:italic>\n                        . Due to toxicity concerns, amphotericin B is generally reserved for triazole-recalcitrant infections. Recent laboratory susceptibility tests show an increase in fluconazole resistance, highlighting a need for new treatments. We have developed a large-scale metabolic screening assay under Biosafety Level 3 containment to identify existing drugs with novel activity against\n                        <jats:italic toggle=\"yes\">Coccidioides<\/jats:italic>\n                        spherules. This drug-repurposing approach represents a convenient and cost-effective strategy to increase the available antifungals effective against these infections.\n                      <\/jats:p>\n                    <\/jats:sec>\n                  <\/jats:sec>","DOI":"10.1128\/mbio.00205-25","type":"journal-article","created":{"date-parts":[[2025,3,26]],"date-time":"2025-03-26T10:52:49Z","timestamp":1742986369000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":9,"title":["Discovery of novel antifungal drugs via screening repurposing libraries against\n                    <i>Coccidioides posadasii<\/i>\n                    spherule initials"],"prefix":"10.1128","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4959-3321","authenticated-orcid":false,"given":"Sarah","family":"Saeger","sequence":"first","affiliation":[{"name":"Department of Molecular Microbiology and Immunology, South Texas Center for Emerging Infectious Diseases, The University of Texas at San Antonio","place":["San Antonio, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kathryn","family":"West-Jeppson","sequence":"additional","affiliation":[{"name":"Department of Molecular Microbiology and Immunology, South Texas Center for Emerging Infectious Diseases, The University of Texas at San Antonio","place":["San Antonio, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu-Rou","family":"Liao","sequence":"additional","affiliation":[{"name":"Department of Molecular Microbiology and Immunology, South Texas Center for Emerging Infectious Diseases, The University of Texas at San Antonio","place":["San Antonio, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Althea","family":"Campuzano","sequence":"additional","affiliation":[{"name":"Department of Molecular Microbiology and Immunology, South Texas Center for Emerging Infectious Diseases, The University of Texas at San Antonio","place":["San Antonio, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jieh-Juen","family":"Yu","sequence":"additional","affiliation":[{"name":"Department of Molecular Microbiology and Immunology, South Texas Center for Emerging Infectious Diseases, The University of Texas at San Antonio","place":["San Antonio, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1992-3270","authenticated-orcid":true,"given":"Jose","family":"Lopez-Ribot","sequence":"additional","affiliation":[{"name":"Department of Molecular Microbiology and Immunology, South Texas Center for Emerging Infectious Diseases, The University of Texas at San Antonio","place":["San Antonio, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1091-3420","authenticated-orcid":true,"given":"Chiung-Yu","family":"Hung","sequence":"additional","affiliation":[{"name":"Department of Molecular Microbiology and Immunology, South Texas Center for Emerging Infectious Diseases, The University of Texas at San Antonio","place":["San Antonio, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.3390\/jof9010083"},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.3390\/jof8080859"},{"key":"e_1_3_4_4_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0247263"},{"key":"e_1_3_4_5_2","doi-asserted-by":"publisher","DOI":"10.1093\/cid\/ciu681"},{"key":"e_1_3_4_6_2","doi-asserted-by":"publisher","DOI":"10.1093\/mmy\/myy095"},{"key":"e_1_3_4_7_2","doi-asserted-by":"publisher","DOI":"10.1007\/978-1-4684-4982-2_12"},{"key":"e_1_3_4_8_2","doi-asserted-by":"publisher","DOI":"10.3201\/eid1206.060028"},{"key":"e_1_3_4_9_2","doi-asserted-by":"publisher","DOI":"10.1093\/mmy\/myy029"},{"key":"e_1_3_4_10_2","doi-asserted-by":"publisher","DOI":"10.7326\/0003-4819-124-3-199602010-00004"},{"key":"e_1_3_4_11_2","doi-asserted-by":"publisher","DOI":"10.1175\/wcas-d-20-0036.1"},{"key":"e_1_3_4_12_2","doi-asserted-by":"publisher","DOI":"10.1093\/ofid\/ofaa623"},{"key":"e_1_3_4_13_2","doi-asserted-by":"publisher","DOI":"10.3390\/ijerph16071113"},{"key":"e_1_3_4_14_2","doi-asserted-by":"publisher","DOI":"10.1080\/21505594.2016.1235653"},{"key":"e_1_3_4_15_2","doi-asserted-by":"publisher","DOI":"10.1177\/20499361231161387"},{"key":"e_1_3_4_16_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.02634-16"},{"key":"e_1_3_4_17_2","doi-asserted-by":"publisher","DOI":"10.1080\/21505594.2016.1196301"},{"key":"e_1_3_4_18_2","first-page":"603","article-title":"Antifungal agents for the treatment of systemic fungal infections in children","volume":"15","author":"Allen U","year":"2010","unstructured":"Allen U. 2010. 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