Department of Veterinary and Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Stigbøjlen 4, DK-1870 Frederiksberg C, Denmark.
Latvian Institute of Organic Synthesis, Aizkraukles 21, 1006 Riga, Latvia.
Int J Mol Sci. 2021 May 25;22(11):5617. doi: 10.3390/ijms22115617.
Infections with enterococci are challenging to treat due to intrinsic resistance to several antibiotics. Especially vancomycin-resistant and are of considerable concern with a limited number of efficacious therapeutics available. From an initial screening of 20 peptidomimetics, 11 stable peptide/β-peptoid hybrids were found to have antibacterial activity against eight and isolates. Microbiological characterization comprised determination of minimal inhibitory concentrations (MICs), probing of synergy with antibiotics in a checkerboard assay, time-kill studies, as well as assessment of membrane integrity. isolates proved more susceptible than isolates, and no differences in susceptibility between the vancomycin-resistant (VRE) and -susceptible isolates were observed. A test of three peptidomimetics (Ac-[hArg-βNsce]-NH, Ac-[hArg-βNsce-Lys-βNspe]-NH and Oct-[Lys-βNspe]-NH) in combination with conventional antibiotics (vancomycin, gentamicin, ciprofloxacin, linezolid, rifampicin or azithromycin) revealed no synergy. The same three potent analogues were found to have a bactericidal effect with a membrane-disruptive mode of action. Peptidomimetics Ac-[hArg-βNsce-Lys-βNspe]-NH and Oct-[Lys-βNspe]-NH with low MIC values (in the ranges 2-8 µg/mL and 4-16 µg/mL against and , respectively) and displaying weak cytotoxic properties (i.e., <10% hemolysis at a ~100-fold higher concentration than their MICs; IC values of 73 and 41 µg/mL, respectively, against HepG2 cells) were identified as promising starting points for further optimization studies.
肠球菌感染由于对几种抗生素具有内在耐药性而难以治疗。特别是耐万古霉素的 和 ，由于有效的治疗方法有限，因此引起了极大的关注。在对 20 种肽模拟物进行初步筛选后，发现 11 种稳定的肽/β-肽模拟物杂合体对 8 种 和 分离株具有抗菌活性。微生物学特性包括测定最小抑菌浓度（MIC），棋盘试验中与抗生素协同作用的探测，时间杀伤研究以及膜完整性评估。 分离株比 分离株更敏感，并且未观察到耐万古霉素（VRE）和 -敏感 分离株之间的敏感性差异。对三种肽模拟物（Ac-[hArg-βNsce]-NH、Ac-[hArg-βNsce-Lys-βNspe]-NH 和 Oct-[Lys-βNspe]-NH）与常规抗生素（万古霉素、庆大霉素、环丙沙星、利奈唑胺、利福平或阿奇霉素）联合测试未发现协同作用。发现相同的三种有效类似物具有杀菌作用，其作用模式为破坏膜。肽模拟物 Ac-[hArg-βNsce-Lys-βNspe]-NH 和 Oct-[Lys-βNspe]-NH 的 MIC 值较低（分别针对 和 ，范围为 2-8 µg/mL 和 4-16 µg/mL），且细胞毒性较弱（即，在比其 MIC 高约 100 倍的浓度下，溶血率<10％；对 HepG2 细胞的 IC 值分别为 73 和 41 µg/mL），被认为是进一步优化研究的有希望的起点。
