Burns Nicolas, 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. 2024 Dec 2;19(12):e0314474. doi: 10.1371/journal.pone.0314474. eCollection 2024.
Aspergillus fumigatus is a widely distributed pathogen responsible for severe infections, particularly in immunocompromised individuals. Triazoles are the primary treatments options for Aspergillus infections; however, the emergence of acquired resistance to this antifungal class is becoming a growing concern. In this study, we investigated the potential of the antiviral drug, lopinavir (LPV) to restore the susceptibility of A. fumigatus strains to a set of azoles, while also reducing the required azole dosage for treatment of susceptible isolates. The combination of LPV with either itraconazole (ITC) or posaconazole (POS) demonstrated potent synergistic interactions against 16 out of 23 (70%) and 21 out of 23 (91%) A. fumigatus isolates, respectively. Moreover, the combination showed synergistic activity against other clinically important Aspergillus species, including A. niger, A. flavus, and A. brasiliensis. The fractional inhibitory concentration index (FICI) for the combinations ranged from 0.18 to 0.313 for ITC and 0.091 to 0.313 for POS, indicating strong synergistic effects. Further investigation revealed that efflux pump inhibition contributed to the synergy observed between azole and LPV. Morphological examination of the fungal cells subjected to this combinational therapy at sub-inhibitory doses showed the presence of carbohydrate granules/patches. The identification of LPV as a promising adjunct therapy holds promise for addressing the emerging challenge of azole resistance in Aspergillus species and improving treatment outcomes for patients.
烟曲霉是一种广泛分布的病原体，可导致严重感染，尤其是在免疫功能低下的个体中。三唑类药物是治疗曲霉感染的主要选择；然而，对这类抗真菌药物获得性耐药的出现正日益受到关注。在本研究中，我们研究了抗病毒药物洛匹那韦（LPV）恢复烟曲霉菌株对一组唑类药物敏感性的潜力，同时还降低了治疗敏感菌株所需的唑类药物剂量。LPV与伊曲康唑（ITC）或泊沙康唑（POS）联合使用时，分别对23株烟曲霉分离株中的16株（约70%）和21株（约91%）表现出强效协同作用。此外，该联合用药对其他临床上重要的曲霉属物种，包括黑曲霉、黄曲霉和巴西曲霉，也显示出协同活性。ITC联合用药的分数抑菌浓度指数（FICI）范围为0.18至0.313，POS联合用药的FICI范围为0.091至0.313，表明有很强的协同作用。进一步研究表明，外排泵抑制作用促成了唑类药物与LPV之间观察到的协同作用。对接受亚抑菌剂量这种联合治疗的真菌细胞进行形态学检查，发现存在碳水化合物颗粒/斑块。将LPV鉴定为一种有前景的辅助治疗药物，有望应对曲霉属物种中唑类耐药这一新兴挑战，并改善患者的治疗效果。
