Antifungal Activity of Capridine β as a Consequence of Its Biotransformation into Metabolite Affecting Yeast Topoisomerase II Activity

Abstract

In the last few years, increasing importance is attached to problems caused by fungal pathogens. Current methods of preventing fungal infections remain unsatisfactory. There are several antifungal compounds which are highly effective in some cases, however, they have limitations in usage: Nephrotoxicity and other adverse effects. In addition, the frequent use of available fungistatic drugs promotes drug resistance. Therefore, there is an urgent need for the development of a novel antifungal drug with a different mechanism of action, blocking of the fungal DNA topoisomerases activity appear to be a promising idea. According to previous studies on the m-AMSA moderate inhibitory effect on fungal topoisomerase II, we have decided to study Capridine β (also acridine derivative) antifungal activity, as well as its inhibitory potential on yeast topoisomerase II (yTOPOII). Results indicated that Capridine β antifungal activity depends on the kind of strains analyzed (MICs range 0.5–64 μg mL−1) and is related to its biotransformation in the cells. An investigation of metabolite formation, identified as Capridine β reduction product (IE1) by the fungus Candida albicans was performed. IE1 exhibited no activity against fungal cells due to an inability to enter the cells. Although no antifungal activity was observed, in contrast to Capridine β, biotransformation metabolite totally inhibited the yTOPOII-mediated relaxation at concentrations lower than detected for m-AMSA. The closely related Capridine β only slightly diminished the catalytic activity of yTOPOII.

The Effect of Conjugation with Octaarginine, a Cell-Penetrating Peptide on Antifungal Activity of Imidazoacridinone Derivative

“…As previously reported, C-1305 diminished the relaxation reaction by 50% at a concentration of 2.5 μM and totally inhibited human topoisomerase II-mediated relaxation at 10 μM [31] The same level of hTOPO II inhibition ability was determined for C-1311 (IC50 2.5 μg mL −1 6.5 μM) [14]. The previously reported modest inhibitory effect of m-AMSA on yTOPO II [15] indicates that the fungal enzyme might be sufficiently distinct from its human counterpart Our results concerning yeast DNA topoisomerase II inhibition measured by relaxation for C-1311 and C-1305 also suggest differences in sensitivity to the presence of both compounds. Although the human enzyme seemed to be more sensitive than the yeast one, it is likely to find antifungal compounds that are inactive against the former but inhibit the latter.…”

“…Thus, one may conclude that the efficient accumulation of Compound 1-R8 resulted in fungal cell death in contrast to Compound 1 or R8. However, as indicated in Figure 5, there is a greater proportion of cells with an accumulated conjugate than PI-positive cells after 1 h and 3 h. The most effective Compound 1 totally inhibited the yeast topoisomerase II-mediated relaxation (Figure 6) at a concentration of 50 µM, lower than that detected for m-AMSA (IC 50 > 200 µM) [15]. m-AMSA, an acridine derivative, was the first synthetic drug approved for clinical usage that was shown to act as a human topoisomerase II (hTOPO II) inhibitor [17].…”

“…The molecular mechanism of antitumor triazoloacridinone C-1305 and imidazoacridinone C-1311 indicates the formula of a human topoisomerase II-stabilizing complex [14,31]. Cleavable, complex stabilizing drugs are the most important and valuable group The previously reported modest inhibitory effect of m-AMSA on yTOPO II [15] indicates that the fungal enzyme might be sufficiently distinct from its human counterpart. Our results concerning yeast DNA topoisomerase II inhibition measured by relaxation for C-1311 and C-1305 also suggest differences in sensitivity to the presence of both compounds.…”

“…Despite the high efficiency of C-1311 as an anticancer compound [9,10] (it was in phase II clinical trials for the treatment of women with metastatic breast cancer [11]), it, among other things, intercalates into DNA [12,13] and exhibited human topoisomerase inhibition activity [14], it was unable to accumulate in Candida albicans cells and no antifungal activity was observed [8]. The results obtained for capridine β (1-nitro-9-aminoacridine derivative) indicate that not only efficient accumulation, but also the biotransformation into a metabolite that can affect fungal topoisomerase II are important with respect to antifungal activity [15].…”

Candida albicans A Major Fungal Pathogen of Humans

“…C. albicans accounts for ~75% of all Candida infections and is an enormous global health burden, the severity of which continues to escalate. This Special Issue, "Candida albicans: A Major Fungal Pathogen of Humans", combines review articles [3][4][5][6][7] and original research [8][9][10][11][12] to explore recent advances in our understanding of C. albicans morphological switching, nutrient acquisition and metabolism, invasive infection in neonates, antimicrobial host responses and the development of potential therapeutics.…”