Elgammal Yehia, Salama Ehab A, Seleem Mohamed N
Department of Biomedical Sciences and Pathobiology, Virginia-Maryland College of Veterinary Medicine, Virginia Polytechnic Institute and State University, Blacksburg, Virginia, United States of America.
Center for One Health Research, Virginia Polytechnic Institute and State University, Blacksburg, Virginia, United States of America.
PLoS One. 2025 May 29;20(5):e0324080. doi: 10.1371/journal.pone.0324080. eCollection 2025.
Candida auris is an invasive fungal pathogen, representing a global public health threat. It is characterized by high mortality rates among infected individuals, significant antifungal resistance, and a remarkable ability to persist in healthcare environments. While amphotericin B is one of the most powerful antifungal agents for treating Candida infections, approximately 30% of C. auris isolates demonstrate resistance to it. Thus, the development of novel antifungal therapies is vital for tackling its life-threatening infections. In this study, we identified four HIV protease inhibitors (atazanavir, saquinavir, lopinavir and ritonavir) as strong potentiators of amphotericin B against C. auris. A synergistic effect between HIV protease inhibitors and amphotericin B was observed against 15 C. auris isolates with fractional inhibitory concentration index (FICI) ranging from 0.09 to 0.50. Additionally, the combinations between HIV protease inhibitors and amphotericin B showed fungicidal effect, significantly reducing the viable cell count in the time-kill assay within 6 hours. Furthermore, the combinations inhibited biofilm formation of C. auris by 60-75% and exhibited a remarkable suppression of C. albicans hyphae. The in vivo treatment with HIV protease inhibitors combined with amphotericin B resulted in a significant reduction of C. auris colony-forming units (CFU) by 1.7-2.6 Log10 in the C. elegans model. These findings suggest that HIV protease inhibitors, in combination with amphotericin B, are promising candidates for the development of novel antifungal drugs to treat Candida infections.
耳念珠菌是一种侵袭性真菌病原体，对全球公共卫生构成威胁。其特点是感染个体死亡率高、具有显著的抗真菌耐药性，并且在医疗环境中具有很强的存活能力。虽然两性霉素B是治疗念珠菌感染最有效的抗真菌药物之一，但约30%的耳念珠菌分离株对其耐药。因此，开发新型抗真菌疗法对于应对其危及生命的感染至关重要。在本研究中，我们确定了四种HIV蛋白酶抑制剂（阿扎那韦、沙奎那韦、洛匹那韦和利托那韦）为两性霉素B抗耳念珠菌的强效增效剂。观察到HIV蛋白酶抑制剂与两性霉素B对15株耳念珠菌分离株具有协同作用，其部分抑菌浓度指数（FICI）范围为0.09至0.50。此外，HIV蛋白酶抑制剂与两性霉素B的组合显示出杀菌作用，在时间杀菌试验中6小时内可显著降低活菌数。此外，这些组合可抑制耳念珠菌生物膜形成60 - 75%，并对白色念珠菌菌丝有显著抑制作用。在秀丽隐杆线虫模型中，用HIV蛋白酶抑制剂联合两性霉素B进行体内治疗可使耳念珠菌集落形成单位（CFU）显著减少1.7 - 2.6个对数10。这些发现表明，HIV蛋白酶抑制剂与两性霉素B联合使用有望成为开发治疗念珠菌感染新型抗真菌药物的候选方案。
