Department of Biotechnology & Food Engineering, Technion-Israel Institute of Technology, Haifa, 32000, Israel.
Sci Rep. 2017 May 19;7(1):2198. doi: 10.1038/s41598-017-02373-0.
Previous studies of the oligoacyllysyl (OAK) series acyl-lysyl-lysyl-aminoacyl-lysine-amide, suggested their utility towards generating robust linear lipopeptide-like alternatives to antibiotics, although to date, none exhibited potent broad-spectrum bactericidal activity. To follow up on this premise, we produced a new analog (CKKcK) and investigated its properties in various media. Mechanistic studies suggest that CKKcK uses a non-specific membrane-disruptive mode of action for rapidly reducing viability of Gram-negative bacteria (GNB) similarly to polymyxin B (PMB), a cyclic lipopeptide used as last resort antibiotic. Indeed, CKKcK displayed similar affinity for lipopolysaccharides and induced cell permeabilization associated with rapid massive membrane depolarization. Unlike PMB however, CKKcK was also bactericidal to Gram-positive bacteria (GPB) at or near the minimal inhibitory concentration (MIC), as assessed against a multispecies panel of >50 strains, displaying MIC at 3 and 6 µM, respectively for GPB and GNB. CKKcK retained activity in human saliva, reducing the viability of cultivable oral microflora by >99% within two minutes of exposure, albeit at higher concentrations, which, nonetheless, were similar to the commercial gold standard, chlorhexidine. This equipotent bactericidal activity was also observed in pre-formed biofilms of Streptococcus mutans, a major periodontal pathogen. Such compounds therefore, may be useful for eradication of challenging poly-microbial infections.
先前对寡聚酰基辅酶（OAK）系列酰基辅酶赖氨酸赖氨酸氨基酰基辅酶赖氨酸酰胺的研究表明，它们可用于生成强大的线性脂肽样抗生素替代品，尽管迄今为止，没有一种表现出强效广谱杀菌活性。为了跟进这一前提，我们生产了一种新的类似物（CKKcK），并在各种介质中研究了其性质。机制研究表明，CKKcK 采用非特异性的膜破坏作用模式，迅速降低革兰氏阴性菌（GNB）的活力，类似于多粘菌素 B（PMB），PMB 是一种用作最后手段的抗生素的环状脂肽。事实上，CKKcK 对脂多糖具有相似的亲和力，并诱导与快速大量膜去极化相关的细胞通透性。然而，与 PMB 不同的是，CKKcK 对革兰氏阳性菌（GPB）也具有杀菌作用，接近最小抑菌浓度（MIC），对 50 多种多菌种的药敏试验表明，GPB 和 GNB 的 MIC 分别为 3 和 6 μM。CKKcK 在人唾液中保持活性，在暴露两分钟内将可培养的口腔微生物群的活力降低>99%，尽管浓度较高，但与商业黄金标准洗必泰相似。在变形链球菌形成的预形成生物膜中也观察到这种等效杀菌活性，变形链球菌是一种主要的牙周病原体。因此，这些化合物可能有助于根除具有挑战性的多微生物感染。
