In vitro and in vivo Efficacy of a Synergistic Combination of Itraconazole and Verapamil Against Aspergillus fumigatus
| Autor: | Hong Sang, Qiuqiong Zeng, Ling Lu, Nanbiao Long, Zheng Zhang, Peiying Chen |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
Microbiology (medical)
verapamil Itraconazole Antifungal drug drug combination lcsh:QR1-502 Pharmacology Aspergillosis Microbiology lcsh:Microbiology Aspergillus fumigatus 03 medical and health sciences chemistry.chemical_compound In vivo synergism medicine Original Research 030304 developmental biology chemistry.chemical_classification 0303 health sciences Ergosterol biology 030306 microbiology bioluminescence imaging biology.organism_classification medicine.disease itraconazole chemistry Azole Verapamil medicine.drug |
| Zdroj: | Frontiers in Microbiology, Vol 10 (2019) Frontiers in Microbiology |
| DOI: | 10.3389/fmicb.2019.01266/full |
| Popis: | The incidence of aspergillosis continues to rise sharply, while the progress made in expanding the antifungal drug arsenal remains extremely slow, indicating an urgent need for new strategies. Previous studies have shown that the calcium signaling pathway, which is evolutionarily conserved in mammals and fungi, is involved in regulating the tolerance of azoles in fungi. In this study, we performed a preliminary screening among various combinations of different clinical calcium channel blockers and different antifungal drugs. We found that the combination of itraconazole and verapamil showed the best synergistic effect against Aspergillus fumigatus. Thereafter, using the checkboard assays we observed synergistic effects of the combination treatment against most of the A. fumigatus strains tested, including itraconazole-sensitive and itraconazole-resistant strains, with a fractional inhibitory concentration index (FICI) < 0.5. Furthermore, we showed that verapamil strongly decreased the cytosolic calcium transients following itraconazole stimulation by an aequorin-mediated method. Moreover, verapamil influenced the efflux of rhodamine 6G, an azole mimic substance. An ergosterol assay revealed that verapamil alone had no effect on ergosterol biosynthesis, but the combination of itraconazole and verapamil treatment decreased the ergosterol level. Further murine assays were performed using a luciferase-probed bioluminescence imaging method. Drug combination therapy reduced lung burden and improved survival rate. In conclusion, verapamil is a promising candidate to enhance the antifungal activity of itraconazole against A. fumigatus. In addition, our study suggests the effectiveness of an emerging approach based on bioluminescence imaging in monitoring the efficacy of drug combination therapy for invasive aspergillosis. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|