A representative of arylcyanomethylenequinone oximes effectively inhibits growth and formation of hyphae in Candida albicans and influences the activity of protein kinases in vitro

Abstract

In this study, we applied various assays to reveal new activities of phenylcyanomethylenequinone oxime-4-(hydroxyimino) cyclohexa-2,5-dien-1-ylidene](phenyl)ethanenitrile () for potential anti-microbial applications. These assays demonstrated (a) the antimicrobial effect on bacterial and fungal cultures, (b) the effect on the activity of the kinase CK2, (c) toxicity towards human erythrocytes, the Caco-2 cancer cell line, and embryonic development of Zebrafish. We demonstrated the activity of against selected bacteria and spp. The MIC ranging from 4 µg/ml to 125 µg/ml proved effective in inhibition of formation of hyphae and cell aggregation in, which was demonstrated at the cytological level. Noteworthy, was found to inhibit the CK2 kinase with moderate potency. Moreover, at low concentrations, it did not exert any evident toxic effects on human erythrocytes, Caco-2 cells, or Zebrafish embryos. can be a potential candidate as a novel drug against infections.

Antifungal Agent 4-AN Changes the Genome-Wide Expression Profile, Downregulates Virulence-Associated Genes and Induces Necrosis in Candida albicans Cells

“…Gene-expression profiling experiments can reveal three main groups of responses: (i) responses consistent with the mechanisms of action of a compound, (ii) responses indicative of other pathways that may be affected by an agent and (iii) responses that reflect mechanisms of resistance to a drug [ 19 ]. In the case of 4-AN, the suggested mechanism of action in C. albicans cells is downregulation of cellular phosphorylation through inhibition of the activity of some protein kinases [ 9 , 10 ]. Since protein kinases can act as transcriptional factors or they regulate the activity of many transcriptional factors via phosphorylation, a decrease in the cellular activity of these enzymes can significantly disturb the expression of genes [ 20 , 21 , 22 ].…”

“…Since protein kinases can act as transcriptional factors or they regulate the activity of many transcriptional factors via phosphorylation, a decrease in the cellular activity of these enzymes can significantly disturb the expression of genes [ 20 , 21 , 22 ]. For example, protein kinase CK2—which is inhibited by 4-AN—upregulates the specific DNA-binding activity of the TATA-binding protein (TBP) by direct phosphorylation of this protein in yeast, which in turn activates RNA polymerase II [ 9 , 23 ]. Another kinase that is targeted by 4-AN is DYRK1A, and the Candida equivalent of the kinase is YAK1 [ 9 ].…”

“…For example, protein kinase CK2—which is inhibited by 4-AN—upregulates the specific DNA-binding activity of the TATA-binding protein (TBP) by direct phosphorylation of this protein in yeast, which in turn activates RNA polymerase II [ 9 , 23 ]. Another kinase that is targeted by 4-AN is DYRK1A, and the Candida equivalent of the kinase is YAK1 [ 9 ]. Genome-wide analysis of DYRK1A-associated loci reveals that the kinase is recruited preferentially to promoters of genes actively transcribed by RNA polymerase II.…”

“…The 4-AN shows high anti- C. albicans activity with minimal inhibitory concentration/minimal fungicidal concentration (MIC/MFC) values of 4/4 µg/mL and effectively disturbs hyphal growth at the 4-AN concentration of MIC/16. Concurrently, at the effective anti- C. albicans doses, the compound does not exert any toxic effect on either human erythrocytes or Zebrafish embryos [ 9 ]. Since the structure of 4-AN resembles known protein kinase inhibitors on the one hand and the phosphorylation status of some Candida proteins correlates with fungal pathogenicity on the other hand, we examined the ability of 4-AN to inhibit protein kinases.…”

Multi-epitope Peptide Vaccine Prediction for Candida albicans targeting Pyruvate Kinase Protein; an Immunoinformatics Approach

“…In addition, Disseminated invasive candidiasis that is a major complication of the disease has an estimated mortality rate of 40%-60% even with the use of antifungal drugs. 1-5 it occurs with various other manifestations ranging from vaginal infections, which affect up to 75% of the women at least once in their lifetime, to deep systemic infections in hospitalized patients leading to high morbidity and mortality rates specially, in immunocompromised individuals, including organ recipients and HIV patients 1,2, [6][7][8][9][10][11][12][13] Three proteins are most likely to be immunogenic in candida albicans which are the fructose-bisphosphate aldolase (Fba1), the phosphoglycerate kinase (Pgk) and the pyruvate kinase (Pk) with (pk) and (Fba1) being more immunodominant . 11,14 PK a 504 bp long, highly conservative protein which catalyzes the final step in glycolysis, converting phosphoenolpyruvate (PEP) and adenosine diphosphate (ADP) to pyruvate and adenosine triphosphate (ATP), once pyruvate is synthesized; it is either fed into the tri-carboxylic acid (TCA) cycle for oxidative phosphorylation or reduced to lactate under anaerobic conditions by lactate dehydrogenase enzyme LDH.…”