Zheng Yan-Qing, Li Qiang-Guo, Latge Jean-Paul, Tang Xi-Ke, Najwa Al-Odaini, Pan Kai-Su, Yang Shi-Xiong, Cao Cun-Wei
Department of Dermatology and Venereology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China.
Infectious Disease Research Laboratory, The Fourth People's Hospital of Nanning, Nanning, Guangxi, China.
J Antimicrob Chemother. 2025 Apr 2;80(4):976-979. doi: 10.1093/jac/dkaf022.
The use of fluconazole for long-term oral candidiasis treatment in HIV/AIDS patients can potentially affect the clearance rate and antifungal efficacy of voriconazole against Talaromyces marneffei infection. We isolated two T. marneffei strains that were both resistant to fluconazole and voriconazole. To investigate the mechanism underlying the induction of the cross-resistance in T. marneffei.
Fluconazole-resistant strains were induced in vitro. The target enzyme 14-α sterol demethylase Cyp51B was sequenced, and drug efflux pump expression was determined by RT-qPCR in all strains.
The sensitivity of fluconazole-induced resistant strains to fluconazole was greater than 128 mg/L, and this resistance was stably inherited after fluconazole pressure was removed. MICs of voriconazole for resistant strains were 4∼16 times greater than FRR (0.25-1 versus 0.06 mg/L). Two mutation hotspots in Cyp51B were detected: G441D and G441V. The AtrF, Mdr1 and Pmfcz genes were significantly overexpressed in the vast majority of the fluconazole-resistant strains (P < 0.05).
The growth of T. marneffei in the presence of fluconazole could induce voriconazole resistance in vitro. The main cause of this cross-resistance in T. marneffei appears to be related to a mutation in Cyp51B at G441 and overexpression of the efflux pumps AtrF, Mdr1 and Pmfcz.
在人类免疫缺陷病毒/获得性免疫综合征（HIV/AIDS）患者中，使用氟康唑长期治疗口腔念珠菌病可能会影响伏立康唑对马尔尼菲篮状菌感染的清除率和抗真菌疗效。我们分离出了两株对氟康唑和伏立康唑均耐药的马尔尼菲篮状菌菌株。为了探究马尔尼菲篮状菌中交叉耐药诱导的潜在机制。
在体外诱导出氟康唑耐药菌株。对靶酶14-α固醇去甲基酶Cyp51B进行测序，并通过逆转录定量聚合酶链反应（RT-qPCR）测定所有菌株中药物外排泵的表达。
氟康唑诱导的耐药菌株对氟康唑的敏感性大于128mg/L，且在去除氟康唑压力后这种耐药性能够稳定遗传。耐药菌株对伏立康唑的最低抑菌浓度（MIC）比氟康唑敏感参考菌株（FRR，0.25 - 1mg/L对比0.06mg/L）高4至16倍。在Cyp51B中检测到两个突变热点：G441D和G441V。在绝大多数氟康唑耐药菌株中，AtrF、Mdr1和Pmfcz基因显著过表达（P<0.05）。
在氟康唑存在的情况下，马尔尼菲篮状菌的生长可在体外诱导对伏立康唑的耐药性。马尔尼菲篮状菌中这种交叉耐药的主要原因似乎与Cyp51B基因G441位点的突变以及外排泵AtrF、Mdr1和Pmfcz的过表达有关。
