Abstract
Acridine cell-penetrating peptide conjugates are an extremely important family of compounds in antitumor chemotherapy. These conjugates are not so widely analysed in antimicrobial therapy, although bioactive peptides could be used as nanocarriers to smuggle antimicrobial compounds. An octaarginine conjugate of an imidazoacridinone derivative (Compound 1-R8) synthetized by us exhibited high antifungal activity against reference and fluconazole-resistant clinical strains (MICs ≤ 4 μg mL−1). Our results clearly demonstrate the qualitative difference in accumulation of the mother compound and Compound 1-R8 conjugate into fungal cells. Only the latter was transported and accumulated effectively. Microscopic and flow cytometry analysis provide some evidence that the killing activity of Compound 1-R8 may be associated with a change in the permeability of the fungal cell membrane. The conjugate exhibited low cytotoxicity against human embryonic kidney (HEK-293) and human liver (HEPG2) cancer cell lines. Nevertheless, the selectivity index value of the conjugate for human pathogenic strains remained favourable and no hemolytic activity was observed. The inhibitory effect of the analysed compound on yeast topoisomerase II activity suggested its molecular target. In summary, conjugation with R8 effectively increased imidazoacridinone derivative ability to enter the fungal cell and achieve a concentration inside the cell that resulted in a high antifungal effect.
Highlights
The discovery of amphotericin B, an antimycotic antibiotic, is considered to be one of the greatest scientific achievements of the 20th century
Despite the high efficiency of C-1311 as an anticancer compound [9,10], 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 clearly indicate that fungal cells can be effectively and selectively killed by our imidazoacridinone-based octaarginine conjugate
Summary
The discovery of amphotericin B, an antimycotic antibiotic, is considered to be one of the greatest scientific achievements of the 20th century. Frequent and inadequate use of antifungals with a broad spectrum of activity has led to drug resistance among many species of fungi. Acridine and acridinone derivatives are a class of compounds with a broad spectrum of biological activity and are very interesting for scientists. Concerning their mode of action, these compounds are able to render DNA damage, disrupt DNA repair and replication, inhibit topoisomerase I and II enzymes [1], and induce cell death [2]. The results obtained for capridine β (1-nitro-9-aminoacridine derivative) indicate that efficient accumulation, and the biotransformation into a metabolite that can affect fungal topoisomerase
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