Antiarrhythmic drug amiodarone displays antifungal activity, induces irregular calcium response and intracellular acidification of Aspergillus niger - amiodarone targets calcium and pH homeostasis of A. niger.
The rapidly developing resistance of fungi to antifungal drugs is a serious health problem. Today's drugs mainly target cell membrane composition and synthesis. Moreover, some of them have serious side effects. New antifungal drugs targeting different molecular pathways are necessary. Amiodarone, an FDA approved antiarrhythmic drug displays antifungal activity. It targets calcium and pH homeostasis. In concentrations above 25 μM, it inhibits the growth of the filamentous fungi Aspergillus niger. It triggers a biphasic calcium response accompanied by a high [Ca(2+)](c) resting level and an intracellular acidification from 7.5 to 6.0, both of which are concentration dependent. Both extracellular calcium and calcium from intracellular organelles are sources of the transient second cytosolic calcium peak, whose amplitude is 0.12 μM for cells treated with 0.1mM amiodarone. In P-type ATPase deficient A. niger strains pmrAΔ and pmcAΔ, the [Ca(2+)](c) resting level after amiodarone treatment is at least twice as high as that of the wild type, which correlates with fungal viability and hypersensitivity to amiodarone. A combination of amiodarone and amphotericin B is additive in terms of cell viability and cytosolic calcium influx. In contrast, a combination of azole drugs and amiodarone has a synergistic effect on the viability of fungi.
Department of Biotechnology, National Institute of Chemistry, Hajdrihova 19, SI-1000 Ljubljana, Slovenia.
Tanja
T
Bagar
Mojca
M
Benčina
D000136:Acid-Base Equilibrium / Q000187:drug effects; D000638:Amiodarone / Q000494:pharmacology*; D000666:Amphotericin B / Q000494:pharmacology; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D000935:Antifungal Agents / Q000494:pharmacology*; D001234:Aspergillus niger / Q000187:drug effects* / Q000254:growth & development / Q000378:metabolism; D001393:Azoles / Q000494:pharmacology; D002118:Calcium / Q000032:analysis / Q000378:metabolism*; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D005656:Fungal Proteins / Q000235:genetics; D006706:Homeostasis / Q000187:drug effects*; D006801:Humans; D006863:Hydrogen-Ion Concentration / Q000187:drug effects; D050296:Microbial Viability / Q000187:drug effects; D008954:Models, Biological; D053499:Plasma Membrane Calcium-Transporting ATPases / Q000235:genetics; D017384:Sequence Deletion; D013312:Stress, Physiological / Q000187:drug effects; D013997:Time Factors
D000889:Anti-Arrhythmia Agents; D000935:Antifungal Agents; D001393:Azoles; D005656:Fungal Proteins; C433210:pmrA protein, Aspergillus niger; D000666:Amphotericin B; D053499:Plasma Membrane Calcium-Transporting ATPases; D000638:Amiodarone; D002118:Calcium