National Clinical Research Center for Laboratory Medicine, State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Department of Laboratory Medicine, the First Hospital of China Medical University, Shenyang, People's Republic of China.
NHC Key Laboratory of AIDS Prevention and Treatment, The First Hospital of China Medical University, China Medical University, Shenyang, People's Republic of China.
Emerg Microbes Infect. 2024 Dec;13(1):2398596. doi: 10.1080/22221751.2024.2398596. Epub 2024 Sep 9.
The global rate of Amphotericin B (AmB) resistance in has surpassed 12%. However, there is limited data on available clinical treatments and microevolutionary analyses concerning reduced AmB sensitivity. In this study, we collected 18 isolates from five patients between 2019 and 2022. We employed clinical data mining, genomic, and transcriptomic analyses to identify genetic evolutionary features linked to reduced AmB sensitivity in these isolates during clinical treatment. We identified six isolates with a minimum inhibitory concentration (MIC) of AmB below 0.5 µg/mL (AmB) and 12 isolates with an AmB-MIC of 1 µg/mL (AmB) or ≥ 2 µg/mL (AmB). All five patients received 24-hour AmB (5 mg/L) bladder irrigation treatment. Evolutionary analyses revealed an (c923t) mutation in AmB . Additionally, AmB was found to contain a t2831c mutation in the gene. In the AmB group, membrane lipid-related gene expression ( and ) was upregulated, while in the AmB group, expression of DNA-related genes (e.g. and ) was up-regulated. In a series of strains with reduced susceptibility to AmB, five key genes were identified: two upregulated ( and and three downregulated (and . In this study, we demonstrate the microevolution of reduced AmB sensitivity in vivo and further elucidate the relationship between reduced AmB sensitivity and low-concentration AmB bladder irrigation. These findings offer new insights into potential antifungal drug targets and clinical markers for the "super fungus", .
全球范围内的两性霉素 B（AmB）耐药率已经超过 12%。然而，关于降低 AmB 敏感性的可用临床治疗方法和微观进化分析的数据有限。在这项研究中，我们收集了 2019 年至 2022 年间 5 名患者的 18 株分离株。我们采用临床数据挖掘、基因组和转录组分析方法，鉴定了这些分离株在临床治疗过程中与降低 AmB 敏感性相关的遗传进化特征。我们鉴定出 6 株 AmB 最小抑菌浓度（MIC）低于 0.5μg/mL（AmB），12 株 AmB-MIC 为 1μg/mL（AmB）或≥2μg/mL（AmB）的分离株。所有 5 名患者均接受 24 小时 AmB（5mg/L）膀胱冲洗治疗。进化分析显示两性霉素 B 基因（c923t）突变。此外，AmB 基因中还发现了 t2831c 突变。在 AmB 组中，膜脂质相关基因表达（和）上调，而在 AmB 组中，DNA 相关基因（如和）表达上调。在一系列对 AmB 敏感性降低的菌株中，鉴定出 5 个关键基因：2 个上调（和和 3 个下调（和。在这项研究中，我们证明了体内降低 AmB 敏感性的微观进化，并进一步阐明了降低 AmB 敏感性与低浓度 AmB 膀胱冲洗之间的关系。这些发现为潜在的抗真菌药物靶点和临床标志物提供了新的见解，对于“超级真菌”具有重要意义。
