Toyotome Takahito, Takahashi Hiroki, Watanabe Akira, Hagiwara Daisuke
Department of Pharmaceutical Sciences, School of Pharmacy at Narita, International University of Health and Welfare, Narita, Chiba Prefecture, Japan.
Department of Veterinary Medicine, Obihiro University of Agriculture and Veterinary Medicine, Obihiro, Hokkaido Prefecture, Japan.
Microbiol Spectr. 2025 Aug 21:e0181025. doi: 10.1128/spectrum.01810-25.
is a common environmental fungus and the leading cause of aspergillosis, an opportunistic infection in humans and animals. The mortality rate of aspergillosis remains high despite antifungal treatments, with azole antifungals, such as voriconazole, being the primary treatment. However, resistance to azoles is increasing, partly because of environmental exposure to agricultural fungicides. In a previous study, we identified the protein RttA to be involved in azole susceptibility. To further understand the role of RttA in azole resistance, we conducted RNA-Seq analysis and functional analyses by constructing RttA deletion and overexpression strains. The transcriptome data revealed that RttA contains a Zn-Cys domain and may function as a transcription factor. Furthermore, six genes, including a γ-glutamyl transpeptidase gene () and a homolog of factor C (), were shown to be putatively regulated by RttA. These findings suggest that RttA is involved in azole resistance by regulating several genes, highlighting its potential as a target for developing antifungal strategies against .IMPORTANCEThis study identified RttA as a Zn-Cys transcription factor in , a critical pathogen that causes aspergillosis. RttA influences azole susceptibility. Our results demonstrated that the deletion of RttA increases susceptibility to azoles, whereas its overexpression enhances resistance. This discovery is crucial because the mechanism underlying azole resistance has not yet been fully elucidated. Hence, understanding the role of RttA provides insights into resistance mechanisms and potential targets for new therapeutic strategies, thereby addressing the urgent need for effective treatments against azole-resistant strains.
是一种常见的环境真菌，也是曲霉病的主要病因，曲霉病是人和动物的一种机会性感染。尽管有抗真菌治疗，但曲霉病的死亡率仍然很高，唑类抗真菌药（如伏立康唑）是主要治疗药物。然而，对唑类的耐药性正在增加，部分原因是环境中接触到农业杀菌剂。在先前的一项研究中，我们确定蛋白质RttA与唑类敏感性有关。为了进一步了解RttA在唑类耐药性中的作用，我们通过构建RttA缺失和过表达菌株进行了RNA测序分析和功能分析。转录组数据显示，RttA含有一个锌-半胱氨酸结构域，可能作为转录因子发挥作用。此外，包括一个γ-谷氨酰转肽酶基因（）和一个C因子同源物（）在内的六个基因被证明可能受RttA调控。这些发现表明，RttA通过调控多个基因参与唑类耐药性，突出了其作为开发针对曲霉病抗真菌策略靶点的潜力。重要性本研究确定RttA是曲霉病关键病原体中的一种锌-半胱氨酸转录因子。RttA影响唑类敏感性。我们的结果表明，RttA的缺失增加了对唑类的敏感性，而其过表达增强了耐药性。这一发现至关重要，因为唑类耐药性的潜在机制尚未完全阐明。因此，了解RttA的作用有助于深入了解耐药机制和新治疗策略的潜在靶点，从而满足针对唑类耐药菌株有效治疗的迫切需求。
