Department of Comparative Pathobiology, College of Veterinary Medicine, Purdue University, West Lafayette, IN, 47907, USA.
Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, Purdue University, West Lafayette, Indiana, 47907, USA.
Sci Rep. 2020 May 5;10(1):7525. doi: 10.1038/s41598-020-64571-7.
The limited number of antifungals and the rising frequency of azole-resistant Candida species are growing challenges to human medicine. Drug repurposing signifies an appealing approach to enhance the activity of current antifungal drugs. Here, we evaluated the ability of Pharmakon 1600 drug library to sensitize an azole-resistant Candida albicans to the effect of fluconazole. The primary screen revealed 44 non-antifungal hits were able to act synergistically with fluconazole against the test strain. Of note, 21 compounds, showed aptness for systemic administration and limited toxic effects, were considered as potential fluconazole adjuvants and thus were termed as "repositionable hits". A follow-up analysis revealed pitavastatin displaying the most potent fluconazole chemosensitizing activity against the test strain (ΣFICI 0.05) and thus was further evaluated against 18 isolates of C. albicans (n = 9), C. glabrata (n = 4), and C. auris (n = 5). Pitavastatin displayed broad-spectrum synergistic interactions with both fluconazole and voriconazole against ~89% of the tested strains (ΣFICI 0.05-0.5). Additionally, the pitavastatin-fluconazole combination significantly reduced the biofilm-forming abilities of the tested Candida species by up to 73%, and successfully reduced the fungal burdens in a Caenorhabditis elegans infection model by up to 96%. This study presents pitavastatin as a potent azole chemosensitizing agent that warrant further investigation.
抗真菌药物的种类有限，而唑类耐药念珠菌的出现频率不断上升，这给人类医学带来了巨大的挑战。药物再利用是提高现有抗真菌药物活性的一种有吸引力的方法。在这里，我们评估了 Pharmakon 1600 药物库增强唑类耐药白色念珠菌对氟康唑敏感性的能力。初步筛选发现，有 44 种非抗真菌药物能够与氟康唑协同作用，对测试菌株发挥作用。值得注意的是，有 21 种化合物具有全身给药的潜力，且毒性有限，被认为是潜在的氟康唑佐剂，因此被称为“可再定位的命中物”。后续分析显示，匹伐他汀对测试菌株显示出最强的氟康唑化学增敏活性（ΣFICI 0.05），因此进一步针对 18 株白色念珠菌（n = 9）、近平滑念珠菌（n = 4）和耳念珠菌（n = 5）进行了评估。匹伐他汀与氟康唑和伏立康唑均显示出广谱协同相互作用，对约 89%的测试菌株（ΣFICI 0.05-0.5）均有效。此外，匹伐他汀-氟康唑联合用药可使测试念珠菌的生物膜形成能力降低高达 73%，并可使秀丽隐杆线虫感染模型中的真菌负荷降低高达 96%。本研究表明匹伐他汀是一种有效的唑类化学增敏剂，值得进一步研究。
