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However, the mechanisms of tolerance and its evolutionary role in acquired resistance in pathogenic fungi, and particularly in filamentous fungi, remain elusive. Here, we identified an\n                      <jats:underline>In<\/jats:underline>\n                      hibitor of\n                      <jats:underline>G<\/jats:underline>\n                      rowth domain-containing protein (IngB) as a novel epigenetic regulator of azole tolerance in\n                      <jats:italic toggle=\"yes\">Aspergillus fumigatus<\/jats:italic>\n                      . The loss of\n                      <jats:italic toggle=\"yes\">ingB<\/jats:italic>\n                      promotes supra-MIC growth on agar surfaces despite susceptible MICs in standardized assays. Moreover, established \u0394\n                      <jats:italic toggle=\"yes\">ingB<\/jats:italic>\n                      biofilms are also less susceptible to azoles\n                      <jats:italic toggle=\"yes\">in vitro<\/jats:italic>\n                      . In a murine model of invasive pulmonary aspergillosis, loss of\n                      <jats:italic toggle=\"yes\">ingB<\/jats:italic>\n                      results in higher pulmonary fungal levels when animals are treated with voriconazole compared to the wild-type control. Subsequent exposure of the \u0394\n                      <jats:italic toggle=\"yes\">ingB<\/jats:italic>\n                      -tolerant strain to high azole concentrations\n                      <jats:italic toggle=\"yes\">in vitro<\/jats:italic>\n                      resulted in rapid acquired resistance, most notably driven by a frameshift mutation in a putative 20S proteasome maturation protein-encoding gene,\n                      <jats:italic toggle=\"yes\">ump<\/jats:italic>\n                      A, while the susceptible wild-type strain failed to acquire adaptive mutations. The data suggest that loss of IngB provides an epistatic background for the emergence of azole resistance. Our work shows that drug tolerance in a critical fungal pathogen can facilitate azole resistance emergence.\n                    <\/jats:p>\n                    <jats:sec>\n                      <jats:title>IMPORTANCE<\/jats:title>\n                      <jats:p>\n                        While antimicrobial drug resistance causes adverse effects on human health, drug tolerance can also lead to insufficient pathogen clearance, resulting in infection relapse. However, the mechanisms of antifungal drug tolerance and its evolutionary role in acquired drug resistance in pathogenic fungi, particularly the molds, remain elusive. We identified IngB as a novel regulator of azole tolerance in\n                        <jats:italic toggle=\"yes\">Aspergillus fumigatus<\/jats:italic>\n                        . In a murine model of invasive pulmonary aspergillosis treated with voriconazole, loss of\n                        <jats:italic toggle=\"yes\">ingB<\/jats:italic>\n                        facilitated higher fungal burden levels than the wild-type control, suggesting the observed\n                        <jats:italic toggle=\"yes\">in vitro<\/jats:italic>\n                        tolerance translates to the murine pulmonary environment. Importantly, loss of IngB leads to rapid azole drug resistance under azole-selective pressure\n                        <jats:italic toggle=\"yes\">in vitro<\/jats:italic>\n                        and led to the discovery of a new gene associated with azole resistance,\n                        <jats:italic toggle=\"yes\">umpA<\/jats:italic>\n                        . Our work identifies a novel regulator of antifungal tolerance in a critical human fungal pathogen and suggests that drug tolerance can pave the way for resistance emergence.\n                      <\/jats:p>\n                    <\/jats:sec>\n                  <\/jats:sec>","DOI":"10.1128\/mbio.00661-26","type":"journal-article","created":{"date-parts":[[2026,6,15]],"date-time":"2026-06-15T12:00:40Z","timestamp":1781524840000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":0,"title":["An epigenetic mechanism of azole tolerance facilitates acquired antifungal resistance in\n                    <i>Aspergillus fumigatus<\/i>"],"prefix":"10.1128","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7025-4450","authenticated-orcid":false,"given":"Sandeep","family":"Vellanki","sequence":"first","affiliation":[{"name":"Department of Microbiology and Immunology, Geisel School of Medicine at 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