Department of Pharmaceutical Sciences, School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Ribeirão Preto, 14040-903, Brazil.
Department of Genetics, Ribeirão Preto Medical School, National Institute of Science and Technology in Stem Cell and Cell Therapy, University of São Paulo, Ribeirão Preto, 14049-900, Brazil.
Braz J Microbiol. 2021 Jun;52(2):491-501. doi: 10.1007/s42770-021-00459-6. Epub 2021 Mar 2.
Filamentous fungus Purpureocillium lilacinum is an emerging pathogen that infects immunocompromised and immunocompetent individuals and is resistant to several azole molecules. Although azole resistance mechanisms are well studied in Aspergillus sp. and Candida sp., there are no studies to date reporting P. lilacinum molecular response to these molecules. The aim of this study was to describe P. lilacinum molecular mechanisms involved in antifungal response against fluconazole and itraconazole. Transcriptomic analyses showed that gene expression modulation takes place when P. lilacinum is challenged for 12 h with fluconazole (64 μg/mL) or itraconazole (16 μg/mL). The antifungals acted on the ergosterol biosynthesis pathway, and two homologous genes coding for cytochrome P450 51 enzymes were upregulated. Genes coding for efflux pumps, such as the major facilitator superfamily transporter, also displayed increased expression in the treated samples. We propose that P. lilacinum develops antifungal responses by raising the expression levels of cytochrome P450 enzymes and efflux pumps. Such modulation could confer P. lilacinum high levels of target enzymes and could lead to the constant withdrawal of antifungals, which would force an increase in the administration of antifungal medications to achieve fungal morbidity or mortality. The findings in this work could aid in the decision-making for treatment strategies in cases of P. lilacinum infection.
丝状真菌亮紫青霉是一种新兴的病原体，可感染免疫功能低下和免疫功能正常的个体，且对几种唑类分子具有耐药性。虽然唑类耐药机制在曲霉属和念珠菌属中研究得很好，但迄今为止，尚无研究报道亮紫青霉对这些分子的分子反应。本研究旨在描述亮紫青霉对抗真菌药物氟康唑和伊曲康唑的抗真菌反应所涉及的分子机制。转录组分析表明，当亮紫青霉受到氟康唑（64μg/mL）或伊曲康唑（16μg/mL）挑战 12 小时时，基因表达发生了调节。这些抗真菌药物作用于麦角固醇生物合成途径，两种编码细胞色素 P450 51 酶的同源基因被上调。在处理样本中，还显示出编码外排泵的基因（如主要易化因子超家族转运蛋白）的表达增加。我们提出，亮紫青霉通过提高细胞色素 P450 酶和外排泵的表达水平来产生抗真菌反应。这种调节可能赋予亮紫青霉高水平的靶酶，并可能导致不断撤出抗真菌药物，这将迫使增加抗真菌药物的使用，以实现真菌发病率或死亡率。本研究的结果可能有助于在亮紫青霉感染的情况下做出治疗策略的决策。
