Terbinafine resistance mediated by salicylate 1-monooxygenase in Aspergillus nidulans
Terbinafine resistance mediated by salicylate 1-monooxygenase in Aspergillus nidulans
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DOI：
10.1128/aac.48.9.3530-3535.2004
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发表时间：
2004-09-01
影响因子：
4.9
通讯作者：
Martinez-Rossi, NM
中科院分区：
文献类型：
--
作者：
Graminha, MAS;Rocha, EMF;Martinez-Rossi, NM
抗真菌药物耐药性是一个反复出现的和日益严重的问题，患者全身真菌感染。紫外线诱导的构巢曲霉耐特比萘芬突变体已被确定，我们在这里报告的一个这样的基因的表征。一个同胞选择的，6.6 kb的基因组DNA片段编码水杨酸1-单加氧酶（salA），和脂肪酸合酶亚基（fasC）赋予特比萘芬抗性转化敏感菌株。携带salA但不携带fasC的亚片段赋予特比萘芬抗性。saL 4作为染色体VI上的单拷贝基因存在，并且编码473个氨基酸的蛋白质，其与水杨酸1-单加氧酶同源，水杨酸1-单加氧酶是细菌中充分表征的萘降解酶。saL 4转录物积累分析显示，在野生型和UV诱导的突变体Terb 7中的特比萘芬依赖性诱导，以及在含有saL 4亚基因组DNA片段的菌株中的过表达，这可能是由于转化事件引起的多拷贝效应。另外的萘降解酶编码基因存在于真菌基因组中，这表明耐药性可能遵循特比萘芬中所含萘环的降解。
Resistance to antifungal agents is a recurring and growing problem among patients with systemic fungal infections. UV-induced Aspergillus nidulans mutants resistant to terbinafine have been identified, and we report here the characterization of one such gene. A sib-selected, 6.6-kb genomic DNA fragment encodes a salicylate 1-monooxygenase (salA), and a fatty acid synthase subunit (fasC) confers terbinafine resistance upon transformation of a sensitive strain. Subfragments carrying salA but not fasC confer terbinafine resistance. saL4 is present as a single-copy gene on chromosome VI and encodes a protein of 473 amino acids that is homologous to salicylate 1-monooxygenase, a well-characterized naphthalene-degrading enzyme in bacteria. saL4 transcript accumulation analysis showed terbinafine-dependent induction in the wild type and the UV-induced mutant Terb7, as well as overexpression in a strain containing the saL4 subgenomic DNA fragment, probably due to the multicopy effect caused by the transformation event. Additional naphthalene degradation enzyme-coding genes are present in fungal genomes, suggesting that resistance could follow degradation of the naphthalene ring contained in terbinafine.