In the fungal pathogen Aspergillus fumigatus, resistance to azole antifungals is often linked to mutations in CYP51A, a gene that encodes the azole antifungal drug target lanosterol 14α-demethylase. The aim of this study was to investigate whether similar changes could be associated with azole resistance in a Malaysian Fusarium solani species complex (FSSC) isolate collection. Most (11 of 15) clinical FSSC isolates were Neocosmospora keratoplastica and the majority (6 of 10) of environmental isolates were Neocosmospora suttoniana strains. All 25 FSSC isolates had high minimum inhibitory concentrations (MICs) for itraconazole and posaconazole, low MICs for amphotericin B, and various (1 to >32 mg/l) voriconazole susceptibilities. There was a tight association between a 23 bp CYP51A promoter deletion and high (>32 mg/l) voriconazole MICs; of 19 FSSC strains sequenced, nine isolates had voriconazole MICs > 32 mg/l, and they all contained the 23 bp CYP51A promoter deletion, although it was absent in the ten remaining isolates with low (≤12 mg/l) voriconazole MICs. Surprisingly, this association between voriconazole resistance and the 23 bp CYP51A promoter deletion held true across species boundaries. It was randomly distributed within and across species boundaries and both types of FSSC isolates were found among environmental and clinical isolates. Three randomly selected N. keratoplastica isolates with low (≤8 mg/l) voriconazole MICs had significantly lower (1.3-7.5 times) CYP51A mRNA expression levels than three randomly selected N. keratoplastica isolates with high (>32 mg/l) voriconazole MICs. CYP51A expression levels, however, were equally strongly induced (~6,500-fold) by voriconazole in two representative strains reaching levels, after 80 min of induction, that were comparable to those of CYP51B. Our results suggest that FSSC isolates with high voriconazole MICs have a 23 bp CYP51A promoter deletion that provides a potentially useful marker for voriconazole resistance in FSSC isolates. Early detection of possible voriconazole resistance is critical for choosing the correct treatment option for patients with invasive fusariosis.

中文翻译：

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与新霉菌性角膜塑形瘤的临床和环境分离物中的伏立康唑抗性相关的23 bp cyp51A启动子缺失。

在真菌病原体烟曲霉中，对吡咯类抗真菌药的耐药性通常与CYP51A的突变相关，CYP51A是一种编码吡咯类抗真菌药靶标羊毛甾醇14α-脱甲基酶的基因。这项研究的目的是调查在马来西亚茄枯萎病菌种复合物（FSSC）分离物中，类似的变化是否可能与吡咯抗性有关。大多数（15个中的11个）临床FSSC分离株是角膜新孢子虫，环境分离物中的大多数（10个中的6个）是suttoniana菌株。所有25个FSSC分离株对伊曲康唑和泊沙康唑的最低抑菌浓度（MICs）高，对两性霉素B的最低MICs低，伏立康唑敏感性高（1至> 32 mg / l）。CYP51A启动子缺失23 bp与伏立康唑MIC高（> 32 mg / l）之间存在紧密的联系; 在测序的19株FSSC菌株中，有9株具有伏立康唑MICs> 32 mg / l的菌株，它们都含有23 bp CYP51A启动子缺失，尽管其余10株具有低伏立康唑MICs（≤12mg / l）的菌株都不存在。令人惊讶的是，伏立康唑抗药性与23 bp CYP51A启动子缺失之间的这种联系在整个物种边界上均成立。它随机分布在物种边界内和跨物种边界，在环境和临床分离株中都发现了两种类型的FSSC分离株。伏立康唑MIC低（≤8mg / l）的三种随机选择的角膜霉菌分离株比伏立康唑MIC高（> 32 mg / l）的3种随机选择的角膜霉菌分离株的CYP51A mRNA表达水平明显降低（1.3-7.5倍） 。但是，CYP51A的表达水平受到了同样的强烈诱导（〜6，在诱导80分钟后，伏立康唑在两个代表性菌株中的表达水平达到CYP51B的500倍）。我们的结果表明，具有较高伏立康唑MIC的FSSC分离株具有23 bp的CYP51A启动子缺失，为FSSC分离株中的伏立康唑耐药性提供了潜在的有用标记。早期检测伏立康唑耐药性对于为浸润性融合症患者选择正确的治疗选择至关重要。