Chen Peiying, Liu Musang, Zeng Qiuqiong, Zhang Zheng, Liu Weida, Sang Hong, Lu Ling
Department of Dermatology, Jinling Hospital, School of Medicine, Nanjing University, Nanjing, China.
Department of Medical Mycology, Institute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College, Nanjing, China.
Front Microbiol. 2020 Jan 21;10:3127. doi: 10.3389/fmicb.2019.03127. eCollection 2019.
The opportunistic pathogen has developed worldwide resistance to azoles largely through mutations in cytochromeP450 enzyme Cyp51. In this study, we indicated that azole situation results in emergence of azole-resistant mutations. There are previously identified azole-resistant mutations (M220K, M220I, M220R, G54E and G54W mutations) and we successfully identified in this study two new mutations (N248K/V436A, Y433N substitution) conferring azole resistance among 18 independent stable azole-resistant isolates. The model of infection experiment verified that Cyp51A mutations N248K/V436A and Y433N reduce efficacy of azole therapy. In addition, a predicted Cyp51A 3D structural model suggested that Y433N mutation causes the reduced affinities between drug target Cyp51A and azole antifungals. This study suggests that drug selection pressure make it possible to isolate unidentified mutations conferring azole resistance in .
这种机会致病菌已在全球范围内对唑类药物产生耐药性，主要是通过细胞色素P450酶Cyp51的突变。在本研究中，我们指出唑类药物的使用情况导致了唑类耐药突变的出现。之前已鉴定出唑类耐药突变（M220K、M220I、M220R、G54E和G54W突变），并且我们在本研究中成功地在18个独立的稳定唑类耐药分离株中鉴定出两个新的赋予唑类耐药性的突变（N248K/V436A、Y433N替代）。感染实验模型证实，Cyp51A突变N248K/V436A和Y433N降低了唑类治疗的疗效。此外，一个预测的Cyp51A三维结构模型表明，Y433N突变导致药物靶点Cyp51A与唑类抗真菌药物之间的亲和力降低。本研究表明，药物选择压力使得有可能分离出未鉴定的赋予唑类耐药性的突变。
