Lack of Association between Fluconazole Susceptibility and ERG11 Nucleotide Polymorphisms in Cryptococcus neoformans Clinical Isolates from Uganda.
Lack of Association between Fluconazole Susceptibility and ERG11 Nucleotide Polymorphisms in Cryptococcus neoformans Clinical Isolates from Uganda.
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乌干达新型隐球菌临床分离株中氟康唑敏感性与ERG11核苷酸多态性缺乏相关性
DOI：
10.3390/jof8050508
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发表时间：
2022-05-15
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--
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在乌干达等资源有限的地区，氟康唑是隐球菌性脑膜炎(CM)单一预防的首选药物。在临床分离株中观察到与新生隐球菌ERG11基因(CYP51)突变有关的新出现的氟康唑耐药性。目前，隐球菌属的单核苷酸多态性(SNPs)研究较少。可能导致氟康唑耐药的ERG11基因在乌干达新生葡萄球菌临床分离株中的特征较差。如果这些信息可用，将有助于管理艾滋病毒患者中的隐球菌病。这项横断面研究调查了新生链球菌ERG11基因编码区的SNPs，以确定已发现的SNPs与临床分离株氟康唑敏感性的关系。对从HIV和隐球菌性脑膜炎患者脑脊液中分离到的310株新生隐球菌属进行了检测。采用微量稀释法测定氟康唑的半数最大抑菌浓度(IC50范围：0.2 5~32μg/m L)。56.1%的菌株具有较低的~lt；8μg/m l的IC_(50)值，43.9%的菌株具有较高的≥_(8)μg/m l。我们对40株临床分离株的ERG11编码序列进行了扩增和测序。在ERG11基因中发现了新的同义突变和2个错义突变：S460T和A457V。所鉴定的SNPs与体外氟康唑IC50值的差异无关(p=0.179)。
Fluconazole is the drug of choice for cryptococcal meningitis (CM) monoprophylaxis in resource-limited settings such as Uganda. Emerging fluconazole resistance linked to mutations in the Cryptococcus neoformans ERG11 gene (CYP51) has been observed in clinical isolates. Currently, the single nucleotide polymorphisms [SNPs] in the Cryptococcus spp. ERG11 gene that could be responsible for fluconazole resistance are poorly characterized within Ugandan C. neoformans clinical isolates. If available, this information would be useful in the management of cryptococcosis among HIV patients. This cross-sectional study investigates the SNPs present in the coding region of the C. neoformans ERG11 gene to determine the relationship between the SNPs identified and fluconazole susceptibility of the clinical isolates. 310 C. neoformans isolates recovered from the Cerebrospinal Fluid (CSF) of patients with HIV and cryptococcal meningitis were examined. The fluconazole half-maximal inhibitory concentrations (IC50 range: 0.25–32 μg/mL) was determined using the microbroth dilution method. A total of 56.1% of the isolates had low IC50 values of <8 μg/mL while 43.9% had high IC50 values ≥ 8 μg/mL. We amplified and sequenced 600 bp of the ERG11 coding sequence from 40 of the clinical isolates. Novel synonymous and 2 missense mutations, S460T and A457V, were identified in the ERG11 gene. The identified SNPs were not associated with differences in fluconazole IC50 values in vitro (p = 0.179).
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