The Naturally Occurring Host Defense Peptide, LL-37, and Its Truncated Mimetics KE-18 and KR-12 Have Selected Biocidal and Antibiofilm Activities Against Candida albicans, Staphylococcus aureus, and Escherichia coli In vitro.
The Naturally Occurring Host Defense Peptide, LL-37, and Its Truncated Mimetics KE-18 and KR-12 Have Selected Biocidal and Antibiofilm Activities Against Candida albicans, Staphylococcus aureus, and Escherichia coli In vitro.
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DOI：
10.3389/fmicb.2017.00544
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发表时间：
2017
影响因子：
5.2
通讯作者：
Lundy FT
中科院分区：
文献类型：
--
作者：
Luo Y;McLean DT;Linden GJ;McAuley DF;McMullan R;Lundy FT
在公认的天然存在的抗微生物剂类别中，人类宿主防御肽是一个重要的群体，其优势（鉴于其来源）在于它们应易于转化为医药产品。截短形式将显示母体肽的一些生物活性也是合理的，其益处是使用固相化学合成它们的成本较低。测试了宿主防御肽LL-37和两种截短的模拟物KE-18和KR-12对白色念珠菌、金黄色葡萄球菌和大肠杆菌的抑制作用和生物膜特性，这些微生物通常与生物膜相关的感染如呼吸机相关性肺炎（VAP）有关。使用计算机预测工具，基于与亲本肽相比其有利的阳离子性、疏水性比率和两亲性，选择截短肽KE-18和KR-12用于最小抑菌浓度（MIC）和滤膜测试。分析两种方法用于确定肽对生物膜的功效;结晶紫测定和XTT [2，3-双-（2-甲氧基-4-硝基-5-磺基苯基）-2H-四唑鎓-5-甲酰苯胺]测定。杀生物活性（通过MIC测量）和生物膜活性（通过结晶紫测定测量）似乎是独立的。LL-37对C.白色念珠菌（MIC > 250 μg/ml），但在生物膜预防和生物膜抑制测定中均具有显著效果。KE-18和KR-12对所有三种微生物产生了优越的上级MIC值。只有KE-18在生物膜预防试验中具有显著的效果，即使在亚MIC下也持续存在。KE-18显示与LL-37一样有效地结合脂多糖，并且更有效地结合脂磷壁酸。在测试的浓度下，没有肽显示出对人红细胞的溶血活性。KE-18应该被考虑作为一种天然肽衍生的治疗药物进一步开发，用于预防多物种生物膜相关感染，如VAP。
Amongst the recognized classes of naturally occurring antimicrobials, human host defense peptides are an important group with an advantage (given their source) that they should be readily translatable to medicinal products. It is also plausible that truncated versions will display some of the biological activities of the parent peptide, with the benefit that they are less costly to synthesize using solid-phase chemistry. The host defense peptide, LL-37, and two truncated mimetics, KE-18 and KR-12, were tested for their inhibitory effects and antibiofilm properties against Candida albicans, Staphylococcus aureus, and Escherichia coli, microorganisms commonly implicated in biofilm-related infections such as ventilator-associated pneumonia (VAP). Using in silico prediction tools, the truncated peptides KE-18 and KR-12 were selected for minimum inhibitory concentration (MIC) and antibiofilm testing on the basis of their favorable cationicity, hydrophobic ratio, and amphipathicity compared with the parent peptide. Two methods were analyzed for determining peptide efficacy against biofilms; a crystal violet assay and an XTT [2,3-bis-(2-methoxy-4-nitro-5-sulfophenyl)-2H-tetrazolium-5-carboxanilide] assay. The biocidal activities (measured by MIC) and antibiofilm activities (measured by a crystal violet assay) appeared to be independent. LL-37 had no biocidal action against C. albicans (MIC > 250 μg/ml) but significant effects in both biofilm-prevention and biofilm-inhibition assays. KE-18 and KR-12 yielded superior MIC values against all three microorganisms. Only KE-18 had a significant effect in the biofilm-prevention assay, which persisted even at sub-MICs. Neither of the truncated peptides were active in the biofilm-inhibition assay. KE-18 was shown to bind lipopolysaccharide as effectively as LL-37 and to bind lipoteichoic acid more effectively. None of the peptides showed hemolytic activity against human erythrocytes at the concentrations tested. KE-18 should be considered for further development as a natural peptide-derived therapeutic for prevention of multi-species biofilm-related infections such as VAP.