Azole Resistance Profile of Amino Acid Changes in Aspergillus fumigatus CYP51A Based on Protein Homology Modeling
Azole Resistance Profile of Amino Acid Changes in Aspergillus fumigatus CYP51A Based on Protein Homology Modeling
复制标题
DOI：
10.1128/aac.01599-09
复制
发表时间：
2010-06-01
影响因子：
4.9
通讯作者：
Melchers, Willem J. G.
中科院分区：
文献类型：
--
作者：
Snelders, Eveline;Karawajczyk, Anna;Melchers, Willem J. G.
分子生物学研究表明，烟曲霉中的大多数唑类耐药性与cyp 51 A基因中的氨基酸取代有关。为了解唑类药物的耐药突变，对130株耐药和76株敏感的A.对烟曲霉分离物进行测序。在130株唑类耐药菌株中，105株在启动子区含有34 bp的串联重复序列，在密码子98处含有亮氨酸-组氨酸取代（命名为TR/L98 H）。另外，在12株TR/L98 H耐药株中发现了S297 T和F495 I突变，1株F495 I突变，8株唑类耐药株中发现了G54、G138或M220密码子突变。在3株唑类敏感株中发现E130 D、L252 L和S400 I突变，13株唑类敏感株和1株唑类耐药株中发现F46 Y、G98 G、M172 V、N248 T、D255 E、L358 L、E427 K和C454 C突变。M220和L98 H位于蛋白质的外围，由A.烟曲霉Cyp 51 A蛋白，并预测既不与唑类化合物相互作用，也不影响结构完整性。因此，在唑敏感的A.烟曲霉菌株对唑类药物的耐药性与唑类药物的耐药性无关。基于Cyp 51 A蛋白同源性模型，可以预测突变与唑类耐药性的潜在相关性。
Molecular studies have shown that the majority of azole resistance in Aspergillus fumigatus is associated with amino acid substitutions in the cyp51A gene. To obtain insight into azole resistance mutations, the cyp51A gene of 130 resistant and 76 susceptible A. fumigatus isolates was sequenced. Out of 130 azole-resistant isolates, 105 contained a tandem repeat of 34 bp in the promoter region and a leucine-to-histidine substitution in codon 98 (designated TR/L98H). Additionally, in 12 of these TR/L98H resistant isolates, the mutations S297T and F495I were found, and in 1 isolate, the mutation F495I was found. In eight azole-resistant isolates, known azole resistance mutations were detected in codon G54, G138, or M220. In three azole-susceptible isolates, the mutation E130D, L252L, or S400I was found and in 13 azole-susceptible isolates but also in 1 azole-resistant isolate, the mutations F46Y, G98G, M172V, N248T, D255E, L358L, E427K, and C454C were found. All of the nonsynonymous mutations, apart from the mutations in codons G54, G138, and M220 and L98H, were located at the periphery of the protein, as determined by a structural model of the A. fumigatus Cyp51A protein, and were predicted neither to interact with azole compounds nor to affect structural integrity. Therefore, this wide diversity of mutations in the cyp51A gene in azole-susceptible A. fumigatus isolates is not correlated with azole resistance. Based on the Cyp51A protein homology model, the potential correlation of a mutation to azole resistance can be predicted.