Eldesouky Hassan E, Salama Ehab A, Lanman Nadia A, Hazbun Tony R, Seleem Mohamed N
Department of Comparative Pathobiology, College of Veterinary Medicine, Purdue University, West Lafayette, Indiana, USA.
Department of Biomedical Sciences and Pathobiology, Virginia-Maryland College of Veterinary Medicine, Virginia Polytechnic Institute and State University, Blacksburg, Virginia, USA.
Antimicrob Agents Chemother. 2020 Dec 16;65(1). doi: 10.1128/AAC.00684-20.
The limited therapeutic options and the recent emergence of multidrug-resistant species present a significant challenge to human medicine and underscore the need for novel therapeutic approaches. Drug repurposing appears as a promising tool to augment the activity of current azole antifungals, especially against multidrug-resistant In this study, we evaluated the fluconazole chemosensitization activities of 1,547 FDA-approved drugs and clinical molecules against azole-resistant This led to the discovery that lopinavir, an HIV protease inhibitor, is a potent agent capable of sensitizing to the effect of azole antifungals. At a therapeutically achievable concentration, lopinavir exhibited potent synergistic interactions with azole drugs, particularly with itraconazole against (fractional inhibitory concentration index [ΣFICI] ranged from 0.04 to 0.09). Additionally, the lopinavir/itraconazole combination enhanced the survival rate of -infected by 90% and reduced the fungal burden in infected nematodes by 88.5% (0.05) relative to that of the untreated control. Furthermore, lopinavir enhanced the antifungal activity of itraconazole against other medically important species, including , , , and Comparative transcriptomic profiling and mechanistic studies revealed that lopinavir was able to significantly interfere with the glucose permeation and ATP synthesis. This compromised the efflux ability of and consequently enhanced the susceptibility to azole drugs, as demonstrated by Nile red efflux assays. Altogether, these findings present lopinavir as a novel, potent, and broad-spectrum azole-chemosensitizing agent that warrants further investigation against recalcitrant infections.
有限的治疗选择以及最近出现的多重耐药菌给人类医学带来了重大挑战，并凸显了新型治疗方法的必要性。药物重新利用似乎是增强当前唑类抗真菌药活性的一种有前景的工具，尤其是针对多重耐药菌。在本研究中，我们评估了1547种美国食品药品监督管理局（FDA）批准的药物和临床分子对唑类耐药菌的氟康唑化学增敏活性。这导致发现洛匹那韦，一种HIV蛋白酶抑制剂，是一种能够使耐药菌对唑类抗真菌药的作用敏感的强效药物。在可达到治疗浓度时，洛匹那韦与唑类药物表现出强效协同相互作用，特别是与伊曲康唑针对某菌（分数抑菌浓度指数[ΣFICI]范围为0.04至0.09）。此外，相对于未治疗的对照组，洛匹那韦/伊曲康唑组合使感染该菌的线虫的存活率提高了90%，并使感染线虫中的真菌负荷降低了88.5%（P<0.05）。此外，洛匹那韦增强了伊曲康唑对其他医学上重要的真菌物种的抗真菌活性，包括某菌、某菌、某菌和某菌。比较转录组分析和机制研究表明，洛匹那韦能够显著干扰葡萄糖渗透和ATP合成。这损害了该菌的外排能力，因此增强了对唑类药物的敏感性，尼罗红外排试验证明了这一点。总之，这些发现表明洛匹那韦是一种新型、强效且广谱的唑类化学增敏剂，值得针对难治性真菌感染进行进一步研究。
