Brankiewicz Wioletta, Okońska Joanna, Serbakowska Katarzyna, Lica Jan, Drab Marek, Ptaszyńska Natalia, Łęgowska Anna, Rolka Krzysztof, Szweda Piotr
Department of Pharmaceutical Technology and Biochemistry, Faculty of Chemistry, Gdańsk University of Technology, Narutowicza 11/12, 80-233 Gdańsk, Poland.
Department of Molecular Biochemistry, Faculty of Chemistry, University of Gdansk, 80-308 Gdańsk, Poland.
Pharmaceutics. 2022 Mar 23;14(4):693. doi: 10.3390/pharmaceutics14040693.
Infections of spp. etiology are frequently treated with azole drugs. Among azoles, the most widely used in the clinical scenario remains fluconazole (FLC). Promising results in treatment of dangerous, systemic infections demonstrate the advantages of combined therapies carried out with combinations of at least two different antifungal agents. Here, we report five conjugates composed of covalently linked FLC and cell penetrating or antimicrobial peptide: TP10-7-NH, TP10-NH, LFcinB(2-11)-NH, LFcinB[Nle]-NH, and HLopt2-NH, with aspects of design, chemical synthesis and their biological activities. Two of these compounds, namely FLCpOH-TP10-NH and FLCpOH-TP10-7-NH, exhibit high activity against reference strains and fluconazole-resistant clinical isolates of , including strains overproducing drug transporters. Moreover, both of them demonstrate higher fungicidal effects compared to fluconazole. Analysis performed with fluorescence and scanning electron microscopy as well as flow cytometry indicated the cell membrane as a molecular target of synthesized conjugates. An important advantage of FLCpOH-TP10-NH and FLCpOH-TP10-7-NH is their low cytotoxicity. The IC value for the human cells after 72 h treatment was comparable to the MIC value after 24 h treatment for most strains of . In reported conjugates, FLC was linked to the peptide by its hydroxyl group. It is worth noting that conjugation of FLC by the nitrogen atom of the triazole ring led to practically inactive compounds. Two compounds produced by us and reported herein appear to be potential candidates for novel antifungal agents.
由 属病因引起的感染通常用唑类药物治疗。在唑类药物中，临床应用最广泛的仍是氟康唑（FLC）。在治疗危险的全身性 感染方面取得的有前景的结果表明，至少两种不同抗真菌药物联合使用的联合疗法具有优势。在此，我们报告了五种由共价连接的氟康唑与细胞穿透肽或抗菌肽组成的缀合物：TP10 - 7 - NH、TP10 - NH、LFcinB(2 - 11) - NH、LFcinB[Nle] - NH和HLopt2 - NH，涉及设计、化学合成及其生物学活性等方面。其中两种化合物，即FLCpOH - TP10 - NH和FLCpOH - TP10 - 7 - NH，对 的参考菌株和耐氟康唑临床分离株表现出高活性，包括过度表达药物转运蛋白的菌株。此外，与氟康唑相比，它们都表现出更高的杀菌效果。通过荧光和扫描电子显微镜以及流式细胞术进行的分析表明细胞膜是合成缀合物的分子靶点。FLCpOH - TP10 - NH和FLCpOH - TP10 - 7 - NH的一个重要优点是它们的低细胞毒性。对于大多数 菌株，处理72小时后人细胞的IC值与处理24小时后的MIC值相当。在报道的缀合物中，氟康唑通过其羟基与肽相连。值得注意的是，通过三唑环的氮原子对氟康唑进行缀合会产生几乎无活性的化合物。我们制备并在此报道的两种化合物似乎是新型抗真菌药物的潜在候选物。
