Katragkou Aspasia, McCarthy Matthew, Alexander Elizabeth L, Antachopoulos Charalampos, Meletiadis Joseph, Jabra-Rizk Mary Ann, Petraitis Vidmantas, Roilides Emmanuel, Walsh Thomas J
Transplantation-Oncology Infectious Diseases Program, Division of Infectious Diseases, Weill Cornell Medical Center of Cornell University, New York, NY, USA Infectious Disease Unit, 3rd Department of Pediatrics, Faculty of Medicine, Aristotle University School of Health Sciences, Hippokration Hospital, Thessaloniki, Greece.
Transplantation-Oncology Infectious Diseases Program, Division of Infectious Diseases, Weill Cornell Medical Center of Cornell University, New York, NY, USA.
J Antimicrob Chemother. 2015 Feb;70(2):470-8. doi: 10.1093/jac/dku374. Epub 2014 Oct 6.
Biofilm formation by Candida albicans poses an important therapeutic challenge in human diseases. Typically, conventional antifungal agents encounter difficulty in treating and fully eradicating biofilm-related infections. Novel therapeutic approaches are needed to treat recalcitrant Candida biofilms. Farnesol is a quorum-sensing molecule, which induces apoptosis, inhibits Ras protein pathways and profoundly affects the morphogenesis of C. albicans. We therefore investigated the interactions between farnesol and different classes of antifungal agents.
The combined antifungal effects of triazoles (fluconazole), polyenes (amphotericin B) and echinocandins (micafungin) with farnesol against C. albicans biofilms were assessed in vitro. Antifungal activity was determined by the XTT metabolic assay and confocal microscopy. The nature and the intensity of the interactions were assessed using the Loewe additivity model [fractional inhibitory concentration (FIC) index] and the Bliss independence (BI) model.
Significant synergy was found between each of the three antifungal agents and farnesol, while antagonism was not observed for any of the combinations tested. The greatest synergistic effect was found with the farnesol/micafungin combination, for which the BI-based model showed the observed effects as being 39%-52% higher than expected if the drugs had been acting independently. The FIC indices ranged from 0.49 to 0.79, indicating synergism for farnesol/micafungin and farnesol/fluconazole and no interaction for farnesol/amphotericin B. Structural changes in the biofilm correlated well with the efficacies of these combinations. The maximum combined effect was dependent on the farnesol concentration for micafungin and amphotericin B.
Farnesol exerts a synergistic or additive interaction with micafungin, fluconazole and amphotericin B against C. albicans biofilms, thus warranting further in vivo study.
白色念珠菌形成生物膜给人类疾病治疗带来了重大挑战。通常，传统抗真菌药物在治疗和完全根除与生物膜相关的感染方面存在困难。需要新的治疗方法来治疗顽固性念珠菌生物膜。法尼醇是一种群体感应分子，可诱导细胞凋亡、抑制Ras蛋白途径并深刻影响白色念珠菌的形态发生。因此，我们研究了法尼醇与不同类别的抗真菌药物之间的相互作用。
在体外评估了三唑类（氟康唑）、多烯类（两性霉素B）和棘白菌素类（米卡芬净）与法尼醇联合对白色念珠菌生物膜的抗真菌作用。通过XTT代谢试验和共聚焦显微镜确定抗真菌活性。使用洛氏加和模型[分数抑制浓度（FIC）指数]和布利斯独立性（BI）模型评估相互作用的性质和强度。
三种抗真菌药物中的每一种与法尼醇之间均发现显著协同作用，而所测试的任何组合均未观察到拮抗作用。法尼醇/米卡芬净组合的协同效应最大，基于BI的模型显示，与药物独立作用相比，观察到的效应高出39% - 52%。FIC指数范围为0.49至0.79，表明法尼醇/米卡芬净和法尼醇/氟康唑具有协同作用，而法尼醇/两性霉素B无相互作用。生物膜的结构变化与这些组合的疗效密切相关。最大联合效应取决于米卡芬净和两性霉素B的法尼醇浓度。
法尼醇与米卡芬净、氟康唑和两性霉素B对白色念珠菌生物膜具有协同或相加相互作用，因此值得进一步进行体内研究。
