In vitro assessment of the growth and plasma membrane H+-ATPase inhibitory activity of ebselen and structurally related selenium- and sulfur-containing compounds in Candida albicans.
Ebselen (EB, compound 1) is an investigational organoselenium compound that reduces fungal growth, in part, through inhibition of the fungal plasma membrane H+-ATPase (Pma1p). In the present study, the growth inhibitory activity of EB and of five structural analogs was assessed in a fluconazole (FLU)-resistant strain of Candida albicans (S2). While none of the compounds were more effective than EB at inhibiting fungal growth (IC50∼ 18 μM), two compounds, compounds 5 and 6, were similar in potency. Medium acidification assays performed with S2 yeast cells revealed that compounds 4 and 6, but not compounds 2, 3, or 5, exerted an inhibitory activity comparable to EB (IC50∼ 14 μM). Using a partially purified Pma1p preparation obtained from S2 yeast cells, EB and all the analogs demonstrated a similar inhibitory activity. Taken together, these results indicate that EB analogs are worth exploring further for use as growth inhibitors of FLU-resistant fungi.
Department of Pharmaceutical Sciences, St. John's University, Jamaica, NY, USA.
Natalie N
NN
Orie
Department of Pharmaceutical Sciences, St. John's University, Jamaica, NY, USA.
Andrew R
AR
Warren
Department of Pharmaceutical Sciences, St. John's University, Jamaica, NY, USA.
Jovana
J
Basaric
Department of Pharmaceutical Sciences, St. John's University, Jamaica, NY, USA.
Cesar
C
Lau-Cam
Division of Organic and Pharmaceutical Technology, Faculty of Chemistry, Wrocław University of Technology, Wrocław, Poland.
Magdalena
M
Piętka-Ottlik
Department of Organic Chemistry, Faculty of Chemistry, Wrocław University of Technology, Wrocław, Poland.
Jacek
J
Młochowski
Department of Pharmaceutical Sciences, St. John's University, Jamaica, NY, USA.
Blase
B
Billack
D000935:Antifungal Agents / Q000737:chemistry / Q000494:pharmacology*; D001393:Azoles / Q000737:chemistry / Q000494:pharmacology*; D002176:Candida albicans / Q000187:drug effects* / Q000201:enzymology / Q000254:growth & development; D002462:Cell Membrane / Q000187:drug effects* / Q000201:enzymology; D017077:Culture Media, Conditioned / Q000737:chemistry; D025141:Drug Resistance, Fungal; D015507:Drugs, Investigational / Q000737:chemistry / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D015725:Fluconazole / Q000494:pharmacology; D005656:Fungal Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006574:Heterocyclic Compounds, 2-Ring / Q000737:chemistry / Q000494:pharmacology; D006863:Hydrogen-Ion Concentration; D054833:Isoindoles; D007700:Kinetics; D008826:Microbial Sensitivity Tests; D050296:Microbial Viability / Q000187:drug effects; D015394:Molecular Structure; D016566:Organoselenium Compounds / Q000737:chemistry / Q000494:pharmacology*; D006180:Proton-Translocating ATPases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013844:Thiazoles / Q000737:chemistry / Q000494:pharmacology
C000625729:2-phenyl-7-azabenzisoselenazol-3(2H)-one; D000935:Antifungal Agents; D001393:Azoles; D017077:Culture Media, Conditioned; D015507:Drugs, Investigational; D004791:Enzyme Inhibitors; D005656:Fungal Proteins; D006574:Heterocyclic Compounds, 2-Ring; D054833:Isoindoles; D016566:Organoselenium Compounds; D013844:Thiazoles; C060674:2-phenyl-1,2-benzisothiazol-3-(2H)-one; C042986:ebselen; D015725:Fluconazole; D006180:Proton-Translocating ATPases
Candida albicans; Pma1p; antifungal activity; ebselen; ebselen analogs; fluconazole-resistant; organoselenium compound; organosulfur compound; plasma membrane H+-ATPase