{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,20]],"date-time":"2026-08-20T14:11:12Z","timestamp":1787235072598,"version":"build-2736575974"},"reference-count":79,"publisher":"American Society for Microbiology","issue":"4","license":[{"start":{"date-parts":[[2026,4,7]],"date-time":"2026-04-07T00:00:00Z","timestamp":1775520000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,4,7]],"date-time":"2026-04-07T00:00:00Z","timestamp":1775520000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"funder":[{"DOI":"10.13039\/501100001807","name":"Funda\u00e7\u00e3o de Amparo \u00e0 Pesquisa do Estado de S\u00e3o Paulo","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001807","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["Microbiol Spectr"],"published-print":{"date-parts":[[2026,4,7]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title\/>\n                    <jats:p>\n                      <jats:italic toggle=\"yes\">Aspergillus fumigatus<\/jats:italic>\n                      is the major causative agent of human aspergillosis. Azoles are the first-line therapy, but resistance is increasing. Here, we characterized voriconazole persistence by screening a global collection of 495 clinical and environmental\n                      <jats:italic toggle=\"yes\">A. fumigatus<\/jats:italic>\n                      isolates. We demonstrate two persistence phenotypes: non-growth persisters (NGPs) and slow-growth persisters (SGPs). We focused on nine sequential clinical isolates from a single patient treated with voriconazole for 2 years. Genome sequencing and phylogenomic analyses show that these isolates form a single genetically related population exhibiting within-host diversification. While temporal isolation order does not strictly correlate with genetic relatedness, we observe that increased azole persistence and stress resistance are early adaptive steps in the\n                      <jats:italic toggle=\"yes\">in vivo<\/jats:italic>\n                      evolution of azole resistance, preceding the emergence of voriconazole resistance. Our findings indicate that increased persistence and stress resistance may create a permissive adaptive landscape within the host, highlighting the complex evolutionary dynamics underlying antifungal treatment failure.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>IMPORTANCE<\/jats:title>\n                    <jats:p>\n                      Azole resistance in\n                      <jats:italic toggle=\"yes\">Aspergillus fumigatus<\/jats:italic>\n                      is a major clinical concern; however, treatment failures occur without the presence of classic resistance mutations. This study provides evidence that azole persistence\u2014the ability of susceptible cells to survive drug exposure\u2014and stress resistance precede the\n                      <jats:italic toggle=\"yes\">in vivo<\/jats:italic>\n                      evolution of azole resistance in\n                      <jats:italic toggle=\"yes\">Aspergillus fumigatus<\/jats:italic>\n                      . We identified two persistence types in a global isolate collection and tracked their evolution in a patient over a 2-year period. Our findings reveal that increased voriconazole persistence and stress resistance emerged before the acquisition of the\n                      <jats:italic toggle=\"yes\">cyp51A<\/jats:italic>\n                      resistance mutation. This adaptive phase involved significant transcriptional and metabolic reprogramming, including the upregulation of secondary metabolism. We propose that persistence is not a passive survival state, but an active evolutionary stepping stone that fosters a permissive landscape for the development of resistance. Understanding this \u201cpersistence-first\u201d pathway is crucial for developing more effective diagnostics and therapeutic strategies to combat antifungal treatment failure.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1128\/spectrum.04021-25","type":"journal-article","created":{"date-parts":[[2026,3,16]],"date-time":"2026-03-16T13:00:10Z","timestamp":1773666010000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":2,"title":["Evidence that increased azole persistence and stress resistance precede the\n                    <i>in vivo<\/i>\n                    evolution of azole resistance in\n                    <i>Aspergillus fumigatus<\/i>"],"prefix":"10.1128","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0313-9046","authenticated-orcid":false,"given":"Endrews","family":"Delbaje","sequence":"first","affiliation":[{"name":"Faculdade de Ci\u00eancias Farmac\u00eauticas de Ribeir\u00e3o Preto, Universidade de S\u00e3o Paulo","place":["Ribeirao Preto, Brazil"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"La\u00eds","family":"Pontes","sequence":"additional","affiliation":[{"name":"Faculdade de Ci\u00eancias Farmac\u00eauticas de Ribeir\u00e3o Preto, Universidade de S\u00e3o Paulo","place":["Ribeirao Preto, Brazil"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marcela","family":"Savoldi","sequence":"additional","affiliation":[{"name":"Faculdade de Ci\u00eancias Farmac\u00eauticas de Ribeir\u00e3o Preto, Universidade de S\u00e3o Paulo","place":["Ribeirao Preto, Brazil"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-3070-2508","authenticated-orcid":true,"given":"Sarah","family":"Sedik","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/0168r3w48","id-type":"ROR","asserted-by":"publisher"}],"name":"Division of Infectious Diseases, Department of Internal Medicine, Medical University of Graz","place":["Graz, Austria"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karl","family":"Dichtl","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/02n0bts35","id-type":"ROR","asserted-by":"publisher"}],"name":"Diagnosic and Research Institute for Hygiene, Microbiology and Environmental Medicine, Medical University of Graz","place":["Graz, Austria"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin","family":"Hoenigl","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/0168r3w48","id-type":"ROR","asserted-by":"publisher"}],"name":"Division of Infectious Diseases, Department of Internal Medicine, Medical University of Graz","place":["Graz, Austria"]},{"id":[{"id":"https:\/\/ror.org\/02n0bts35","id-type":"ROR","asserted-by":"publisher"}],"name":"Division of Infectious Diseases and Global Public Health, Department of Medicine, University of California San Diego","place":["La Jolla, USA"]},{"id":[{"id":"https:\/\/ror.org\/0168r3w48","id-type":"ROR","asserted-by":"publisher"}],"name":"Clinical and Translational Fungal Working Group, University of California San Diego","place":["La Jolla, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2946-7785","authenticated-orcid":true,"given":"Cornelia","family":"Lass-Fl\u00f6rl","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/054pv6659","id-type":"ROR","asserted-by":"publisher"}],"name":"Institute of Hygiene and Medical Microbiology, Medical University of Innsbruck","place":["Innsbruck, Austria"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6750-1593","authenticated-orcid":true,"given":"Cristina","family":"Silva Pereira","sequence":"additional","affiliation":[{"name":"Instituto de Tecnologia Qu\u00edmica e Biol\u00f3gica Ant\u00f3nio Xavier, NOVA University Lisbon","place":["Oeiras, Portugal"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5095-5054","authenticated-orcid":true,"given":"Ang\u00e9lica Zaninelli","family":"Schreiber","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/04wffgt70","id-type":"ROR","asserted-by":"publisher"}],"name":"School of Medical Sciences - 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