Departamento de Microbiologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Minas Gerais, Brazil.
Departamento de Microbiologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Minas Gerais, Brazil; Laboratório de Micologia, Universidade Ceuma, São Luís, Maranhão, Brazil.
Int J Antimicrob Agents. 2017 Jun;49(6):695-702. doi: 10.1016/j.ijantimicag.2017.04.005. Epub 2017 Apr 24.
Cryptococcosis caused by Cryptococcus gattii leads to pneumonia and meningoencephalitis, and has a high mortality rate worldwide due to the inadequacy of available therapy and increasing drug resistance. There is a need to develop effective treatments, and drug repositioning is an interesting alternative to achieve new strategies to treat cryptococcosis. Atorvastatin (ATO), a statin currently used to treat hypercholesterolaemia, was tested in this study as an adjuvant to control infections caused by C. gattii. Several aspects of the effect of ATO on the host and the yeast were evaluated, with particular focus on the association of ATO with fluconazole (FLC), which (i) reduced ergosterol content in the cell membrane and altered properties of the polysaccharide capsule of C. gattii; (ii) increased the production of reactive oxygen species by macrophages; and (iii) reduced yeast phagocytosis and the intracellular proliferation rate. In an animal model, infected mice treated with ATO + FLC showed increased survival, improved clinical condition, and reduced fungal burden in the lungs and brain. This study is the first to perform in vivo tests with ATO + FLC for the treatment of cryptococcosis. The results suggest that ATO may be an important adjuvant for the treatment of cryptococcosis.
隐球菌病由新型隐球菌引起，可导致肺炎和脑膜脑炎，由于现有治疗方法的不足和耐药性的增加，全球死亡率很高。因此，有必要开发有效的治疗方法，而药物再定位是实现治疗隐球菌病新策略的一个有趣选择。阿托伐他汀（ATO）是一种目前用于治疗高胆固醇血症的他汀类药物，本研究将其作为辅助药物来控制新型隐球菌引起的感染。评估了 ATO 对宿主和酵母的多个方面的影响，特别关注 ATO 与氟康唑（FLC）的联合作用，该作用（i）降低了细胞膜中的麦角固醇含量并改变了新型隐球菌多糖荚膜的特性；（ii）增加了巨噬细胞中活性氧的产生；（iii）降低了酵母吞噬作用和细胞内增殖速度。在动物模型中，用 ATO+FLC 治疗的感染小鼠的存活率提高，临床状况改善，肺部和脑部的真菌负荷减少。本研究首次对 ATO+FLC 治疗隐球菌病进行了体内试验。结果表明，ATO 可能是治疗隐球菌病的重要辅助药物。
