Verapamil Inhibits Aspergillus Biofilm, but Antagonizes Voriconazole
Hasan Nazik1,2, Varun Choudhary3, David A Stevens4,5
1California Institute for Medical Research, 2260 Clove Dr., San Jose, CA 95128, USA. hasannazik01@gmail.com.
Abstract:
The paucity of effective antifungals against Aspergillus and increasing resistance, the recognition of the importance of Aspergillus biofilm in several clinical settings, and reports of verapamil-a calcium channel blocker-efficacy against Candida biofilm and hyphal growth, and synergy with an azole antifungal in vitro, led to a study of verapamil ± voriconazole against Aspergillus. Broth macrodilution methodology was utilized for MIC (minimum inhibitory concentration) and MFC (minimum fungicidal concentration) determination. The metabolic effects (assessed by XTT [2,3-bis[2-methoxy-4-nitro-5-sulfophenyl]-2H-tetrazolium-5-carboxanilide inner salt]) on biofilm formation by conidia were studied upon exposure to verapamil, verapamil plus voriconazole, or voriconazole alone. For biofilm formation, we found less inhibition from the combinations than with either drug alone, or less inhibition from the combination than that of the more potent drug alone. For preformed biofilm, we found no significant change in activity comparing voriconazole alone compared to added verapamil, and no significant alteration of activity of the more potent voriconazole, at any concentration in the range tested, by addition of a concentration of verapamil that is inhibitory alone. In full checkerboard assays with planktonic fungus, there was no indication of any effect of one drug on the other (indifference). Although verapamil was similarly inactive against planktonic Aspergillus, as with Candida, verapamil was indeed active against Aspergillus biofilm. However, indifference and antagonism was found with voriconazole.
Insights
Verapamil showed activity against Aspergillus biofilms, but combinations with voriconazole did not improve antifungal efficacy. The study found indifference or antagonism between verapamil and voriconazole against Aspergillus.
Area of Science:
- Medical Mycology
- Antifungal Drug Discovery
- Biofilm Research
Background:
- Growing resistance to antifungals against Aspergillus necessitates novel therapeutic strategies.
- Aspergillus biofilms are clinically significant, contributing to persistent infections.
- Verapamil demonstrated efficacy against Candida biofilms, prompting investigation against Aspergillus.
Purpose of the Study:
- To evaluate the efficacy of verapamil, alone and in combination with voriconazole, against Aspergillus.
- To assess the impact of verapamil on Aspergillus biofilm formation and preformed biofilms.
- To determine the in vitro interaction between verapamil and voriconazole against planktonic and biofilm-forming Aspergillus.
Main Methods:
- Broth macrodilution was used to determine minimum inhibitory concentration (MIC) and minimum fungicidal concentration (MFC).
- Metabolic activity of Aspergillus biofilms was assessed using the XTT assay.
- Checkerboard assays evaluated drug interactions against planktonic and biofilm-forming Aspergillus.
Main Results:
- Verapamil demonstrated activity against Aspergillus biofilms, but not against planktonic Aspergillus.
- Combinations of verapamil and voriconazole showed less inhibition of biofilm formation than either drug alone.
- Verapamil did not enhance the activity of voriconazole against preformed Aspergillus biofilms; indifference or antagonism was observed.
Conclusions:
- Verapamil possesses anti-biofilm activity against Aspergillus, independent of its activity against planktonic forms.
- The combination of verapamil and voriconazole does not offer synergistic or additive benefits against Aspergillus biofilms.
- Further research is needed to explore verapamil's role in treating Aspergillus-related biofilm infections.
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