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However, the emergence of azole resistance in\n              <jats:italic>A. fumigatus<\/jats:italic>\n              has become a global health concern despite the low proportion of resistant isolates in natural populations. In bacteria, antibiotic resistance incurs a fitness cost that renders strains less competitive in the absence of antibiotics. Consequently, fitness cost is a key determinant of the spread of resistant mutations. However, the cost of azole resistance and its underlying causes in\n              <jats:italic>A. fumigatus<\/jats:italic>\n              remain poorly understood. In this observation, we revealed that the 10 out of 15 screened azole-resistant isolates, which possessed the most common azole-targeted\n              <jats:italic>cyp51A<\/jats:italic>\n              mutations, particularly the presence of tandem repeats in the promoter region, exhibit fitness cost when competing with the susceptible isolates in azole-free environments. These results suggest that fitness cost may significantly influence the dynamics of azole resistance, which ultimately contributes to the low prevalence of azole-resistant\n              <jats:italic>A. fumigatus<\/jats:italic>\n              isolates in the environment and clinic. By constructing\n              <jats:italic>in situ cyp51A<\/jats:italic>\n              mutations in a parental azole-susceptible strain and reintroducing the wild-type\n              <jats:italic>cyp51A<\/jats:italic>\n              gene into the azole-resistant strains, we demonstrated that fitness cost is not directly dependent on\n              <jats:italic>cyp51A<\/jats:italic>\n              mutations but is instead associated with the evolution of variable mutations related to conidial germination or other unknown development-related processes. Importantly, our observations unexpectedly revealed that some azole-resistant isolates showed no detectable fitness cost, and some even exhibited significantly increased competitive fitness in azole-free environments, highlighting the potential risk associated with the prevalence of these isolates.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>IMPORTANCE<\/jats:title>\n            <jats:p>\n              Azole resistance in the human fungal pathogen\n              <jats:italic>Aspergillus fumigatus<\/jats:italic>\n              presents a global public health challenge. Understanding the epidemic trends and evolutionary patterns of azole resistance is critical to prevent and control the spread of azole-resistant isolates. The primary cause is the mutation of the drug target 14\u03b1-sterol-demethylase Cyp51A, yet its impact on competitive ability remains uncertain. Our competition assays revealed a diverse range of fitness outcomes for environmental and clinical\n              <jats:italic>cyp51A<\/jats:italic>\n              -mutated isolates. We have shown that this fitness cost is not reliant on\n              <jats:italic>cyp51A<\/jats:italic>\n              mutations but might be linked to unknown mutations induced by stress conditions. Among these isolates, the majority displayed fitness costs, while a few displayed enhanced competitive ability, which may have a potential risk of spread and the need to closely monitor these isolates. Our observation reveals the variation in fitness costs among azole-resistant isolates of\n              <jats:italic>A. fumigatus<\/jats:italic>\n              , highlighting the significant role of fitness cost in the spread of resistant strains.\n            <\/jats:p>\n          <\/jats:sec>","DOI":"10.1128\/mbio.00263-24","type":"journal-article","created":{"date-parts":[[2024,2,26]],"date-time":"2024-02-26T14:00:36Z","timestamp":1708956036000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":27,"title":["Variability in competitive fitness among environmental and clinical azole-resistant\n            <i>Aspergillus fumigatus<\/i>\n            isolates"],"prefix":"10.1128","volume":"15","author":[{"given":"Shu","family":"Chen","sequence":"first","affiliation":[{"name":"Jiangsu Key Laboratory for Microbes and Functional Genomics, Jiangsu Engineering and Technology Research Centre for Microbiology, College of Life Sciences, Nanjing Normal University, Nanjing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guoxing","family":"Zhu","sequence":"additional","affiliation":[{"name":"Jiangsu Key Laboratory for Microbes and Functional Genomics, Jiangsu Engineering and Technology Research Centre for Microbiology, College of Life Sciences, Nanjing Normal University, Nanjing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4437-1631","authenticated-orcid":false,"given":"Huiping","family":"Lin","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jian","family":"Guo","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9256-3868","authenticated-orcid":false,"given":"Shuwen","family":"Deng","sequence":"additional","affiliation":[{"name":"The People\u2019s Hospital of SND (Suzhou New District), Suzhou, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenjuan","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2986-350X","authenticated-orcid":true,"given":"Gustavo H.","family":"Goldman","sequence":"additional","affiliation":[{"name":"Faculdade de Ci\u00eancias Farmac\u00eauticas de Ribeir\u00e3o Preto, Universidade de S\u00e3o Paulo, Ribeir\u00e3o Preto, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2891-7326","authenticated-orcid":false,"given":"Ling","family":"Lu","sequence":"additional","affiliation":[{"name":"Jiangsu Key Laboratory for Microbes and Functional Genomics, Jiangsu Engineering and Technology Research Centre for Microbiology, College of Life Sciences, Nanjing Normal University, Nanjing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0854-6123","authenticated-orcid":false,"given":"Yuanwei","family":"Zhang","sequence":"additional","affiliation":[{"name":"Jiangsu Key Laboratory for Microbes and Functional Genomics, Jiangsu Engineering and Technology Research Centre for Microbiology, College of Life Sciences, Nanjing Normal University, Nanjing, 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