Department of Pharmacy and Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
Department of Clinical Pharmacy and Translational Sciences, University of Tennessee Health Science Center, Memphis, Tennessee, USA.
Microbiol Spectr. 2023 Jun 15;11(3):e0518822. doi: 10.1128/spectrum.05188-22. Epub 2023 May 4.
Aspergillus fumigatus is a ubiquitous environmental mold that can cause severe disease in immunocompromised patients and chronic disease in individuals with underlying lung conditions. Triazoles are the most widely used class of antifungal drugs to treat A. fumigatus infections, but their use in the clinic is threatened by the emergence of triazole-resistant isolates worldwide, reinforcing the need for a better understanding of resistance mechanisms. The predominant mechanisms of A. fumigatus triazole resistance involve mutations affecting the promoter region or coding sequence of the target enzyme of the triazoles, Cyp51A. However, triazole-resistant isolates without -associated mutations are frequently identified. In this study, we investigate a pan-triazole-resistant clinical isolate, DI15-105, that simultaneously carries the mutations and , with no mutations in . Using a Cas9-mediated gene-editing system, and mutations were reverted in DI15-105. Here, we show that the combination of these mutations accounts for pan-triazole resistance in DI15-105. To our knowledge, DI15-105 is the first clinical isolate reported to simultaneously carry mutations in and and only the second with the mutation. Triazole resistance is an important cause of treatment failure and high mortality rates for A. fumigatus human infections. Although Cyp51A-associated mutations are frequently identified as the cause of A. fumigatus triazole resistance, they do not explain the resistance phenotypes for several isolates. In this study, we demonstrate that and mutations additively contribute to pan-triazole resistance in an A. fumigatus clinical isolate lacking -associated mutations. Our results exemplify the importance of and the need for a better understanding of -independent triazole resistance mechanisms.
烟曲霉是一种无处不在的环境霉菌，可导致免疫功能低下的患者发生严重疾病，并使肺部基础疾病患者发生慢性疾病。三唑类药物是治疗烟曲霉感染最广泛使用的一类抗真菌药物，但由于世界各地出现了耐三唑类药物的分离株，其临床应用受到威胁，这进一步强调了更好地了解耐药机制的必要性。烟曲霉对三唑类药物耐药的主要机制涉及影响三唑类药物靶酶 Cyp51A 启动子区域或编码序列的突变。然而，经常会发现没有相关突变的耐三唑类药物分离株。在这项研究中，我们研究了一种泛三唑类耐药的临床分离株 DI15-105，该分离株同时携带突变 和 ，而 Cyp51A 中没有突变。使用 Cas9 介导的基因编辑系统，我们在 DI15-105 中反转了 和 突变。在这里，我们表明这些突变的组合导致 DI15-105 对泛三唑类药物的耐药性。据我们所知，DI15-105 是第一个同时携带 和 突变的临床分离株，并且是第二个携带 突变的分离株。三唑类药物耐药是烟曲霉人类感染治疗失败和高死亡率的重要原因。尽管 Cyp51A 相关突变常被认为是烟曲霉对三唑类药物耐药的原因，但它们并不能解释几个分离株的耐药表型。在这项研究中，我们证明 和 突变在缺乏 Cyp51A 相关突变的烟曲霉临床分离株中可协同导致泛三唑类药物耐药。我们的研究结果说明了 -独立的三唑类药物耐药机制的重要性和需要更好地理解这种机制。
