Department of Pharmaceutical Technology and Biochemistry, Faculty of Chemistry and BioTechMed Center, Gdańsk University of Technology, 11/12 Narutowicza Str., 80-233 Gdańsk, Poland.
Department of Inorganic Chemistry, Faculty of Pharmacy, Medical University of Gdańsk, Gen. J. Hallera 107th Avenue, 80-416 Gdańsk, Poland.
Int J Mol Sci. 2021 Dec 7;22(24):13190. doi: 10.3390/ijms222413190.
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 ) synthetized by us exhibited high antifungal activity against reference and fluconazole-resistant clinical strains (MICs ≤ 4 μg mL). Our results clearly demonstrate the qualitative difference in accumulation of the mother compound and Compound 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 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 effectively increased imidazoacridinone derivative ability to enter the fungal cell and achieve a concentration inside the cell that resulted in a high antifungal effect.
吖啶细胞穿透肽缀合物是抗肿瘤化疗中一个极其重要的化合物家族。尽管生物活性肽可用作纳米载体来输送抗菌化合物，但这些缀合物在抗菌治疗中的分析还不那么广泛。我们合成的咪唑并吖啶酮衍生物的八精氨酸缀合物（化合物）对参考和氟康唑耐药的临床菌株表现出很高的抗真菌活性（MICs≤4μg/mL）。我们的结果清楚地表明，母体化合物和化合物缀合物进入真菌细胞的积累存在定性差异。只有后者才能被有效转运和积累。显微镜和流式细胞术分析提供了一些证据，表明化合物的杀伤活性可能与真菌细胞膜通透性的变化有关。该缀合物对人胚肾（HEK-293）和人肝（HEPG2）癌细胞系的细胞毒性较低。然而，该缀合物对人体致病菌株的选择性指数值仍然有利，并且没有观察到溶血活性。分析化合物对酵母拓扑异构酶 II 活性的抑制作用表明了其分子靶标。总之，与有效增加了咪唑并吖啶酮衍生物进入真菌细胞的能力，并在细胞内达到了高抗真菌效果的浓度。
