Department of Biomedical Sciences and Pathobiology, Virginia-Maryland College of Veterinary Medicine, Virginia Polytechnic Institute and State University, Blacksburg, Virginia, USA.
Center for One Health Research, Virginia Polytechnic Institute and State University, Blacksburg, Virginia, USA.
Antimicrob Agents Chemother. 2024 Nov 6;68(11):e0055624. doi: 10.1128/aac.00556-24. Epub 2024 Oct 10.
The emergence of poses a significant health challenge that has led to a new era of multidrug-resistant fungal infections. Invasive infections caused by are usually associated with remarkable morbidity and mortality. For many years, amphotericin B (AmB) remained the most efficient and the last line of treatment against most hard-to-treat fungal infections. However, strains of possess extraordinary resistance to most antifungal agents, including AmB. In this study, we screened 2,600 FDA-approved drugs and clinical compounds to identify the antiemetic drug rolapitant as a promising enhancer to AmB against . Rolapitant exhibited potent synergistic interactions with AmB against all tested (29/29) isolates. In a time-kill assay, rolapitant restored the fungicidal activity of AmB within 4 h. Additionally, the synergistic relationship between rolapitant and AmB was observed against other medically crucial , and species. A transcriptomic study revealed that exposure to rolapitant affects oxidation reduction processes, ion transporters, and ATP production. Rolapitant triggers an elevation in cytosolic and mitochondrial calcium levels and induces oxidative stress within fungal cells. An ATP luminescence assay confirmed that rolapitant, at sub-inhibitory concentrations, significantly interfered with ATP production in . Moreover, rolapitant enhanced the activity of AmB in a mouse model of disseminated infection, as the combination reduced the fungal burden in murine kidneys by ~1 log (90%) colony forming units. Our findings warrant further investigation of using rolapitant to overcome AmB resistance in and other fungal species.
棘白菌素的出现带来了重大的健康挑战，导致了多药耐药真菌感染的新时代。由棘白菌素引起的侵袭性感染通常与显著的发病率和死亡率相关。多年来，两性霉素 B（AmB）仍然是治疗大多数难治性真菌感染最有效和最后的手段。然而，棘白菌素的菌株对大多数抗真菌药物，包括 AmB，具有非凡的耐药性。在这项研究中，我们筛选了2600 种 FDA 批准的药物和临床化合物，以确定止吐药罗来帕替尼（rolapitant）是一种有前途的 AmB 增效剂，用于治疗棘白菌素。罗来帕替尼与 AmB 对所有测试的（29/29）棘白菌素分离株均表现出强大的协同相互作用。在时间杀伤测定中，罗来帕替尼在 4 小时内恢复了 AmB 的杀菌活性。此外，在其他具有重要医学意义的曲霉属、毛霉属和镰孢属物种中，也观察到罗来帕替尼与 AmB 的协同关系。转录组学研究表明，暴露于罗来帕替尼会影响氧化还原过程、离子转运体和 ATP 产生。罗来帕替尼触发细胞溶质和线粒体钙水平升高，并在真菌细胞内诱导氧化应激。ATP 发光测定证实，罗来帕替尼在亚抑制浓度下，显著干扰棘白菌素的 ATP 产生。此外，罗来帕替尼增强了 AmB 在播散性感染的小鼠模型中的活性，因为联合用药使小鼠肾脏中的真菌负荷减少了约 1 对数（90%）集落形成单位。我们的研究结果证明，进一步研究使用罗来帕替尼来克服棘白菌素和其他真菌物种中的 AmB 耐药性是合理的。
