Center for Chemistry and Biomedicine, Department of Pharmaceutical Technology, Institute of Pharmacy, University of Innsbruck, Innrain 80/82, 6020 Innsbruck, Austria.
Biocenter, Institute of Molecular Biology, Medical University of Innsbruck, Innrain 80/82, 6020 Innsbruck, Austria.
J Colloid Interface Sci. 2023 Jan 15;630(Pt B):164-178. doi: 10.1016/j.jcis.2022.10.077. Epub 2022 Oct 19.
Aminoglycosides are well known, cationic antimicrobial drugs. However, biofilm-based antibiotic resistance significantly limits their efficacy. Masking the polycationic character of these drugs, followed by incorporation into self-emulsifying drug delivery systems (SEDDS) can improve biofilm eradication.
Imine derivatives were synthesized via coupling with trans-cinnamaldehyde and characterized regarding degree of substitution, logP, cytotoxicity and antimicrobial efficacy on the opportunistic human pathogens Escherichia coli, Staphylococcus aureus and Candida albicans. Imines were loaded into newly developed SEDDS formulations and the antimicrobial efficacy was assessed on these pathogens in planktonic state and after biofilm formation.
Successful synthesis of imine derivatives with almost entirely masked amine groups was confirmed by NMR, FT-IR, TLC and MS. Imines exhibited a marked elevation in logP value of 8 units for kanamycin and 7.7 units for tobramycin. They showed low toxicity profiles while fully preserving antimicrobial efficacy on all tested pathogens. Incorporation into SEDDS resulted in nanoemulsions, which exhibited equal antimicrobial efficacy on the model germs compared to the corresponding aminoglycosides. Moreover, the biofilm eradication assay revealed superior anti-biofilm properties of the nanoemulsions. Native aminoglycosides were largely prone to reduced microbial susceptibility due to biofilm formation, while the combination of SEDDS with iminated aminoglycosides provided overall enhanced biofilm eradication.
氨基糖苷类抗生素是众所周知的阳离子型抗菌药物。然而，基于生物膜的抗生素耐药性显著限制了它们的疗效。掩蔽这些药物的多阳离子特性，然后将其纳入自乳化药物递送系统（SEDDS）可以提高生物膜的清除率。
通过与反式肉桂醛偶联合成亚胺衍生物，并对取代度、logP、细胞毒性和抗菌功效进行了表征，这些功效针对机会性人类病原体大肠杆菌、金黄色葡萄球菌和白色念珠菌。将亚胺负载到新开发的 SEDDS 配方中，并评估它们在浮游状态和生物膜形成后的这些病原体中的抗菌功效。
通过 NMR、FT-IR、TLC 和 MS 证实了亚胺衍生物的成功合成，几乎完全掩蔽了胺基。亚胺的 logP 值显著提高了 8 个单位，对于卡那霉素和妥布霉素则提高了 7.7 个单位。它们表现出低毒性谱，同时完全保留了对所有测试病原体的抗菌功效。将其纳入 SEDDS 后形成纳米乳液，与相应的氨基糖苷类药物相比，对模型细菌具有同等的抗菌功效。此外，生物膜清除试验显示纳米乳液具有优越的抗生物膜特性。由于生物膜的形成，天然氨基糖苷类药物容易降低微生物的敏感性，而 SEDDS 与亚胺化氨基糖苷类药物的组合则提供了整体增强的生物膜清除率。
