Triazole fungicides can induce cross-resistance to medical triazoles in Aspergillus fumigatus.
Triazole fungicides can induce cross-resistance to medical triazoles in Aspergillus fumigatus.
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DOI：
10.1371/journal.pone.0031801
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Verweij PE
中科院分区：
文献类型：
--
作者：
Snelders E;Camps SM;Karawajczyk A;Schaftenaar G;Kema GH;van der Lee HA;Klaassen CH;Melchers WJ;Verweij PE
唑类化合物在曲霉病的防治中起着重要的作用。氮唑耐药性是烟曲霉的一个新出现的全球性问题，可能会通过患者的治疗而发展。此外，还提出了一种通过接触14种α去甲基酶抑制剂(DMIS)而产生耐药性的环境途径。与这一假定的杀菌剂驱动的途径相关的主要抗性机制是Cyp51a基因(TR34/L98H)的组合变化。我们调查了TR34/L98H是否可能是通过接触DMIS而形成的。对1970年至2005年期间在荷兰被批准用作杀菌剂、除草剂、除草剂安全剂和植物生长调节剂的31种化合物进行了对医用三氮唑的交叉耐药性调查。此外，还进行了CYP51-蛋白质同源模建和分子比对研究，以确定分子结构和对接模式的相似性。丙环唑、溴康唑、戊唑醇、环氧康唑和苯醚甲环唑这五种三氮唑DMIs的分子结构与医用三氮唑非常相似，并且在对接蛋白质时采取了类似的姿势。这些DMIS还显示出最大的交叉耐药性，重要的是，它们在1990年至1996年期间被授权使用，紧接着1998年第一个临床分离株TR34/L98H的恢复。通过对TR34/L98H分离株的微卫星基因分型，我们计算出第一个分离株可能在1997年出现，证实了上述实验的结果。最后，我们进行了诱导实验，以考察在实验室条件下是否可以诱导TR34/L98H。一个分离物从两个串联重复序列进化到三个，这表明杀菌剂的压力确实可以导致这些基因组变化。我们的发现支持杀菌剂驱动的TR34/L98H在烟曲霉菌中的发育途径。5种三氮唑类DMIS与3种医用三氮唑的分子结构特征相似，可能是交叉耐药的潜在机制。我们的发现对评估与使用三氮唑DMIS相关的健康风险具有重大意义。
Azoles play an important role in the management of Aspergillus diseases. Azole resistance is an emerging global problem in Aspergillus fumigatus, and may develop through patient therapy. In addition, an environmental route of resistance development has been suggested through exposure to 14α-demethylase inhibitors (DMIs). The main resistance mechanism associated with this putative fungicide-driven route is a combination of alterations in the Cyp51A-gene (TR34/L98H). We investigated if TR34/L98H could have developed through exposure to DMIs. Thirty-one compounds that have been authorized for use as fungicides, herbicides, herbicide safeners and plant growth regulators in the Netherlands between 1970 and 2005, were investigated for cross-resistance to medical triazoles. Furthermore, CYP51-protein homology modeling and molecule alignment studies were performed to identify similarity in molecule structure and docking modes. Five triazole DMIs, propiconazole, bromuconazole, tebuconazole, epoxiconazole and difenoconazole, showed very similar molecule structures to the medical triazoles and adopted similar poses while docking the protein. These DMIs also showed the greatest cross-resistance and, importantly, were authorized for use between 1990 and 1996, directly preceding the recovery of the first clinical TR34/L98H isolate in 1998. Through microsatellite genotyping of TR34/L98H isolates we were able to calculate that the first isolate would have arisen in 1997, confirming the results of the abovementioned experiments. Finally, we performed induction experiments to investigate if TR34/L98H could be induced under laboratory conditions. One isolate evolved from two copies of the tandem repeat to three, indicating that fungicide pressure can indeed result in these genomic changes. Our findings support a fungicide-driven route of TR34/L98H development in A. fumigatus. Similar molecule structure characteristics of five triazole DMIs and the three medical triazoles appear the underlying mechanism of cross resistance development. Our findings have major implications for the assessment of health risks associated with the use of triazole DMIs.
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影响因子：
11.8
作者：
Denning, David W.;Park, Steven;Perlin, David S.
通讯作者：
Perlin, David S.
影响因子：
11.8
作者：
Pascual, Andres;Calandra, Thierry;Marchetti, Oscar
通讯作者：
Marchetti, Oscar
影响因子：
4.9
作者：
Kuipers, Saskia;Bruggemann, Roger J. M.;Verweij, Paul E.
通讯作者：
Verweij, Paul E.
影响因子：
4.9
作者：
Lockhart, Shawn R.;Frade, Joao P.;Balajee, S. Arunmozhi
通讯作者：
Balajee, S. Arunmozhi
影响因子：
9.4
作者：
de Valk, HA;Meis, JFGM;Klaassen, CHW
通讯作者：
Klaassen, CHW