Aspasia Katragkou1, Matthew McCarthy2, Elizabeth L Alexander3, Charalampos Antachopoulos4, Joseph Meletiadis5, Mary Ann Jabra-Rizk6, Vidmantas Petraitis2, Emmanuel Roilides4, Thomas J Walsh7. 1. 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. 2. Transplantation-Oncology Infectious Diseases Program, Division of Infectious Diseases, Weill Cornell Medical Center of Cornell University, New York, NY, USA. 3. Department of Medicine, Weill Cornell Medical College, New York, NY, USA. 4. Infectious Disease Unit, 3rd Department of Pediatrics, Faculty of Medicine, Aristotle University School of Health Sciences, Hippokration Hospital, Thessaloniki, Greece. 5. Clinical Microbiology Laboratory, Attikon University Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece. 6. Department of Oncology and Diagnostic Sciences, University of Maryland, Baltimore, MD, USA Department of Microbiology and Immunology, School of Medicine, University of Maryland, Baltimore, MD, USA. 7. Transplantation-Oncology Infectious Diseases Program, Division of Infectious Diseases, Weill Cornell Medical Center of Cornell University, New York, NY, USA Department of Pediatrics, Weill Cornell Medical College, New York, NY, USA Department of Microbiology and Immunology, Weill Cornell Medical College, New York, NY, USA thw2003@med.cornell.edu.
Abstract
OBJECTIVES: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: Farnesol exerts a synergistic or additive interaction with micafungin, fluconazole and amphotericin B against C. albicans biofilms, thus warranting further in vivo study.
OBJECTIVES: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS:Farnesol exerts a synergistic or additive interaction with micafungin, fluconazole and amphotericin B against C. albicans biofilms, thus warranting further in vivo study.
Authors: G L Drusano; D Z D'Argenio; W Symonds; P A Bilello; J McDowell; B Sadler; A Bye; J A Bilello Journal: Antimicrob Agents Chemother Date: 1998-09 Impact factor: 5.191
Authors: Daniel D Mosel; Raluca Dumitru; Jacob M Hornby; Audrey L Atkin; Kenneth W Nickerson Journal: Appl Environ Microbiol Date: 2005-08 Impact factor: 4.792
Authors: Joseph Meletiadis; Paul E Verweij; Debbie T A TeDorsthorst; Jacques F G M Meis; Johan W Mouton Journal: Med Mycol Date: 2005-03 Impact factor: 4.076
Authors: H Koo; M F Hayacibara; B D Schobel; J A Cury; P L Rosalen; Y K Park; A M Vacca-Smith; W H Bowen Journal: J Antimicrob Chemother Date: 2003-10-16 Impact factor: 5.790
Authors: Angélica de L Rodríguez López; Myung-Ryul Lee; Nathan B Wang; Kaitlin K Dunn; Hiram Sanchez; Namrata Raman; David R Andes; David M Lynn; Sean P Palecek Journal: Antimicrob Agents Chemother Date: 2019-08-23 Impact factor: 5.191
Authors: Miroslav Mišík; Metka Filipic; Armen Nersesyan; Katarína Mišíková; Siegfried Knasmueller; Michael Kundi Journal: Environ Sci Pollut Res Int Date: 2015-12-01 Impact factor: 4.223
Authors: Marcelo Ernesto Fernández-Rivero; José L Del Pozo; Amparo Valentín; Araceli Molina de Diego; Javier Pemán; Emilia Cantón Journal: J Fungi (Basel) Date: 2017-03-22