Alkashef Nour M, 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. 2024 Aug 1;19(8):e0308216. doi: 10.1371/journal.pone.0308216. eCollection 2024.
Cryptococcosis is a fungal infection that is becoming increasingly prevalent worldwide, particularly among individuals with compromised immune systems, such as HIV patients. Amphotericin B (AmB) is the first-line treatment mainly combined with flucytosine. The scarcity and the prohibitive cost of this regimen urge the use of fluconazole as an alternative, leading to increased rates of treatment failure and relapses. Therefore, there is a critical need for efficient and cost-effective therapy to enhance the efficacy of AmB. In this study, we evaluated the efficacy of the HIV protease inhibitors (PIs) to synergize the activity of AmB in the treatment of cryptococcosis. Five PIs (ritonavir, atazanavir, saquinavir, lopinavir, and nelfinavir) were found to synergistically potentiate the killing activity of AmB against Cryptococcus strains with ƩFICI ranging between 0.09 and 0.5 against 20 clinical isolates. This synergistic activity was further confirmed in a time-kill assay, where different AmB/PIs combinations exhibited fungicidal activity within 24 hrs. Additionally, PIs in combination with AmB exhibited an extended post-antifungal effect on treated cryptococcal cells for approximately 10 hrs compared to 4 hours with AmB alone. This promising activity against cryptococcal cells did not exhibit increased cytotoxicity towards treated kidney cells, ruling out the risk of drug combination-induced nephrotoxicity. Finally, we evaluated the efficacy of AmB/PIs combinations in the Caenorhabditis elegans model of cryptococcosis, where these combinations significantly reduced the fungal burden of the treated nematodes by approximately 2.44 Log10 CFU (92.4%) compared to the untreated worms and 1.40 Log10 ((39.4%) compared to AmB alone. The cost-effectiveness and accessibility of PIs in resource-limited geographical areas compared to other antifungal agents, such as flucytosine, make them an appealing choice for combination therapy.
隐球菌病是一种真菌感染，在全球范围内日益普遍，尤其是在免疫系统受损的个体中，如艾滋病患者。两性霉素B（AmB）是主要与氟胞嘧啶联合使用的一线治疗药物。该治疗方案的稀缺性和高昂成本促使人们使用氟康唑作为替代药物，导致治疗失败和复发率增加。因此，迫切需要高效且具有成本效益的疗法来提高AmB的疗效。在本研究中，我们评估了HIV蛋白酶抑制剂（PIs）在协同AmB治疗隐球菌病方面的疗效。发现五种PIs（利托那韦、阿扎那韦、沙奎那韦、洛匹那韦和奈非那韦）可协同增强AmB对隐球菌菌株的杀伤活性，对20株临床分离株的ƩFICI介于0.09至0.5之间。在时间杀菌试验中进一步证实了这种协同活性，不同的AmB/PIs组合在24小时内表现出杀真菌活性。此外，与单独使用AmB的4小时相比，PIs与AmB联合使用对处理后的隐球菌细胞表现出约10小时的延长抗真菌后效应。这种对隐球菌细胞有前景的活性对处理后的肾细胞未表现出增加的细胞毒性，排除了药物联合诱导肾毒性的风险。最后，我们在秀丽隐杆线虫隐球菌病模型中评估了AmB/PIs组合的疗效，与未处理的线虫相比，这些组合使处理后的线虫真菌负荷显著降低约2.44 Log10 CFU（92.4%），与单独使用AmB相比降低1.40 Log10（39.4%）。与其他抗真菌药物如氟胞嘧啶相比，PIs在资源有限的地理区域具有成本效益和可及性，使其成为联合治疗的有吸引力选择。
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