Fan Yuying, Wang Yue, Korfanty Gregory A, Archer Meagan, Xu Jianping
Department of Biology, McMaster University, Hamilton, ON L8S 4K1, Canada.
Pathogens. 2021 Jun 4;10(6):701. doi: 10.3390/pathogens10060701.
is a ubiquitous fungus and the main agent of aspergillosis, a common fungal infection in the immunocompromised population. Triazoles such as itraconazole and voriconazole are the common first-line drugs for treating aspergillosis. However, triazole resistance in has been reported in an increasing number of countries. While most studies of triazole resistance have focused on mutations in the triazole target gene , >70% of triazole-resistant strains in certain populations showed no mutations in . To identify potential non- mutations associated with triazole resistance in , we analyzed the whole genome sequences and triazole susceptibilities of 195 strains from 12 countries. These strains belonged to three distinct clades. Our genome-wide association study (GWAS) identified a total of six missense mutations significantly associated with itraconazole resistance and 18 missense mutations with voriconazole resistance. In addition, to investigate itraconazole and pan-azole resistance, Fisher's exact tests revealed 26 additional missense variants tightly linked to the top 20 SNPs obtained by GWAS, of which two were consistently associated with triazole resistance. The large number of novel mutations related to triazole resistance should help further investigations into their molecular mechanisms, their clinical importance, and the development of a comprehensive molecular diagnosis toolbox for triazole resistance in .
是一种普遍存在的真菌，也是曲霉病的主要病原体，曲霉病是免疫功能低下人群中常见的真菌感染。伊曲康唑和伏立康唑等三唑类药物是治疗曲霉病的常用一线药物。然而，越来越多的国家报告了对三唑类药物的耐药性。虽然大多数关于三唑类耐药性的研究都集中在三唑类靶基因的突变上，但在某些人群中，超过70%的三唑类耐药菌株在该基因中未显示出突变。为了确定与曲霉中三唑类耐药性相关的潜在非该基因突变，我们分析了来自12个国家的195株菌株的全基因组序列和三唑类药物敏感性。这些菌株属于三个不同的进化枝。我们的全基因组关联研究（GWAS）共鉴定出6个与伊曲康唑耐药性显著相关的错义突变和18个与伏立康唑耐药性相关的错义突变。此外，为了研究伊曲康唑和泛唑耐药性，Fisher精确检验揭示了另外26个与GWAS获得的前20个单核苷酸多态性紧密连锁的错义变异，其中两个与三唑类耐药性始终相关。大量与三唑类耐药性相关的新突变应有助于进一步研究其分子机制、临床重要性以及开发用于曲霉三唑类耐药性的综合分子诊断工具箱。
