Graminha Marcia A S, Rocha Eleusa M F, Prade Rolf A, Martinez-Rossi Nilce M
Departamento de Genética, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, 14049-900 Ribeirão Preto, Sao Paulo, Brazil.
Antimicrob Agents Chemother. 2004 Sep;48(9):3530-5. doi: 10.1128/AAC.48.9.3530-3535.2004.
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. salA 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. salA 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 salA 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.
在患有全身性真菌感染的患者中，对抗真菌药物的耐药性是一个反复出现且日益严重的问题。已鉴定出紫外线诱导的对特比萘芬耐药的构巢曲霉突变体，我们在此报告其中一个此类基因的特征。一个通过同胞选择获得的6.6 kb基因组DNA片段编码一种水杨酸1-单加氧酶（salA），并且一个脂肪酸合酶亚基（fasC）在转化敏感菌株时赋予特比萘芬抗性。携带salA但不携带fasC的亚片段赋予特比萘芬抗性。salA作为单拷贝基因存在于第六条染色体上，编码一个由473个氨基酸组成的蛋白质，该蛋白质与水杨酸1-单加氧酶同源，后者是细菌中一种特征明确的萘降解酶。salA转录本积累分析表明，在野生型和紫外线诱导的突变体Terb7中，特比萘芬依赖性诱导，以及在含有salA亚基因组DNA片段的菌株中过表达，这可能是由于转化事件引起的多拷贝效应。真菌基因组中存在其他萘降解酶编码基因，这表明耐药性可能是由于特比萘芬中含有的萘环降解所致。
