{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T13:54:18Z","timestamp":1791554058620,"version":"4.3.4"},"reference-count":98,"publisher":"American Society for Microbiology","issue":"8","license":[{"start":{"date-parts":[[2024,8,14]],"date-time":"2024-08-14T00:00:00Z","timestamp":1723593600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2024,8,14]],"date-time":"2024-08-14T00:00:00Z","timestamp":1723593600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"funder":[{"name":"HHS | NIH | National Institute of Allergy and Infectious Diseases","award":["AI170543"],"award-info":[{"award-number":["AI170543"]}],"id":[{"id":"https:\/\/ror.org\/043z4tv69","id-type":"ROR","asserted-by":"crossref"}]},{"name":"Astellas | Astellas Pharma Global Development","award":["ISR005855\/CRES-21B01"],"award-info":[{"award-number":["ISR005855\/CRES-21B01"]}]}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["mBio"],"published-print":{"date-parts":[[2024,8,14]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title\/>\n                    <jats:p>\n                      Mucormycoses are emerging fungal infections caused by a variety of heterogeneous species within the Mucorales order. Among the\n                      <jats:italic toggle=\"yes\">Mucor<\/jats:italic>\n                      species complex,\n                      <jats:italic toggle=\"yes\">Mucor circinelloides<\/jats:italic>\n                      is the most frequently isolated pathogen in mucormycosis patients and despite its clinical significance, there is an absence of established genome manipulation techniques to conduct molecular pathogenesis studies. In this study, we generated a spontaneous uracil auxotrophic strain and developed a genetic transformation procedure to analyze molecular mechanisms conferring antifungal drug resistance. With this new model, phenotypic analyses of gene deletion mutants were conducted to define Erg3 and Erg6a as key biosynthetic enzymes in the\n                      <jats:italic toggle=\"yes\">M. circinelloides<\/jats:italic>\n                      ergosterol pathway. Erg3 is a C-5 sterol desaturase involved in growth, sporulation, virulence, and azole susceptibility. In other fungal pathogens,\n                      <jats:italic toggle=\"yes\">erg3<\/jats:italic>\n                      mutations confer azole resistance because Erg3 catalyzes the production of a toxic diol upon azole exposure. Surprisingly,\n                      <jats:italic toggle=\"yes\">M. circinelloides<\/jats:italic>\n                      produces only trace amounts of this toxic diol and yet, it is still susceptible to posaconazole and isavuconazole due to alterations in membrane sterol composition. These alterations are severely aggravated by\n                      <jats:italic toggle=\"yes\">erg3<\/jats:italic>\n                      \u0394 mutations, resulting in ergosterol depletion and, consequently, hypersusceptibility to azoles. We also identified Erg6a as the main C-24 sterol methyltransferase, whose activity may be partially rescued by the paralogs Erg6b and Erg6c. Loss of Erg6a function diverts ergosterol synthesis to the production of cholesta-type sterols, resulting in resistance to amphotericin B. Our findings suggest that mutations or epimutations causing loss of Erg6 function may arise during human infections, resulting in antifungal drug resistance to first-line treatments against mucormycosis.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>IMPORTANCE<\/jats:title>\n                    <jats:p>\n                      The\n                      <jats:italic toggle=\"yes\">Mucor<\/jats:italic>\n                      species complex comprises a variety of opportunistic pathogens known to cause mucormycosis, a potentially lethal fungal infection with limited therapeutic options. The only effective first-line treatments against mucormycosis consist of liposomal formulations of amphotericin B and the triazoles posaconazole and isavuconazole, all of which target components within the ergosterol biosynthetic pathway. This study uncovered\n                      <jats:italic toggle=\"yes\">M. circinelloides<\/jats:italic>\n                      Erg3 and Erg6a as key enzymes to produce ergosterol, a vital constituent of fungal membranes. Absence of any of those enzymes leads to decreased ergosterol and consequently, resistance to ergosterol-binding polyenes such as amphotericin B. Particularly, losing Erg6a function poses a higher threat as the ergosterol pathway is channeled into alternative sterols similar to cholesterol, which maintain membrane permeability. As a result,\n                      <jats:italic toggle=\"yes\">erg6a<\/jats:italic>\n                      mutants survive within the host and disseminate the infection, indicating that Erg6a deficiency may arise during human infections and confer resistance to the most effective treatment against mucormycoses.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1128\/mbio.01661-24","type":"journal-article","created":{"date-parts":[[2024,7,9]],"date-time":"2024-07-09T09:00:39Z","timestamp":1720515639000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":15,"title":["Alternative ergosterol biosynthetic pathways confer antifungal drug resistance in the human pathogens within the\n                    <i>Mucor<\/i>\n                    species complex"],"prefix":"10.1128","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3560-6155","authenticated-orcid":true,"given":"Mar\u00eda Isabel","family":"Navarro-Mendoza","sequence":"first","affiliation":[{"name":"Department of Molecular Genetics and Microbiology, Duke University School of Medicine","place":["Durham, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1384-3608","authenticated-orcid":true,"given":"Carlos","family":"P\u00e9rez-Arques","sequence":"additional","affiliation":[{"name":"Department of Molecular Genetics and Microbiology, Duke University School of Medicine","place":["Durham, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3855-4194","authenticated-orcid":false,"given":"Josie","family":"Parker","sequence":"additional","affiliation":[{"name":"Molecular Biosciences Division, School of Biosciences, Cardiff University","place":["Cardiff, United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ziyan","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Molecular Genetics and Microbiology, Duke University School of Medicine","place":["Durham, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7991-5040","authenticated-orcid":false,"given":"Steven","family":"Kelly","sequence":"additional","affiliation":[{"name":"Institute of Life Science, Swansea University Medical School","place":["Swansea, United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6369-5995","authenticated-orcid":true,"given":"Joseph","family":"Heitman","sequence":"additional","affiliation":[{"name":"Department of Molecular Genetics and Microbiology, Duke University School of Medicine","place":["Durham, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_5_2_2","doi-asserted-by":"publisher","DOI":"10.1093\/cid\/cir866"},{"key":"e_1_3_5_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1473-3099(19)30312-3"},{"key":"e_1_3_5_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/S2666-5247(21)00237-8"},{"key":"e_1_3_5_5_2","doi-asserted-by":"publisher","DOI":"10.3201\/eid2907.221771"},{"key":"e_1_3_5_6_2","volume-title":"WHO fungal priority pathogens list to guide research, development and public health action","author":"World Health Organization","year":"2022","unstructured":"World Health Organization. 2022. 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