Comparison of a Short Linear Antimicrobial Peptide with Its Disulfide-Cyclized and Cyclotide-Grafted Variants against Clinically Relevant Pathogens.
Comparison of a Short Linear Antimicrobial Peptide with Its Disulfide-Cyclized and Cyclotide-Grafted Variants against Clinically Relevant Pathogens.
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DOI：
10.3390/microorganisms9061249
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发表时间：
2021-06-08
期刊：
影响因子：
4.5
通讯作者：
Craik DJ
中科院分区：
文献类型：
--
作者：
Koehbach J;Gani J;Hilpert K;Craik DJ
根据世界卫生组织(世卫组织)的说法，微生物对抗生素产生抗药性是最紧迫的健康问题之一。这种情况将会加剧，因为目前只有几家制药公司在开发新型抗菌化合物。迫切需要发现和开发具有新作用模式的新型抗菌化合物。抗菌肽(AMPs)能够杀死耐多药细菌，因此开发成抗菌药物是人们感兴趣的。这些多肽的蛋白分解稳定性和毒性是需要克服的挑战，其中一个经常被用来解决稳定性的策略是环化。在这里，我们引入了一个二硫键来环化一种有效的、无毒的9肽，此外，作为一项概念验证研究，我们将该肽嫁接到环肽MCoTI-II的环6中。这是首次将抗菌肽成功嫁接到环肽支架上。二硫代环和接枝环肽在发酵液中表现出中等活性，在1/5发酵液中对临床相关耐药病原菌表现出较强的活性。线状多肽在两种条件下均表现出较好的活性。测得其在100%人血清中的半衰期为13分钟，简单二硫键环化肽为9分钟，接枝环肽为7小时15分钟。添加10%的人血清会导致不同生物体的抗菌活性丧失，环肽的抗菌活性从1倍到8倍不等。二硫键环化和线型的活性也有不同程度的下降，分别是2~18倍和1~30倍。尽管稳定性有很大差异，但线型多肽仍显示出优异的抗菌活性。环肽和二硫键环化版本显示出比线性版本更慢的杀菌效果。这三种多肽在高pH和低pH条件下都很稳定，并且具有很低的溶血和细胞毒活性。
According to the World Health Organization (WHO) the development of resistance against antibiotics by microbes is one of the most pressing health concerns. The situation will intensify since only a few pharmacological companies are currently developing novel antimicrobial compounds. Discovery and development of novel antimicrobial compounds with new modes of action are urgently needed. Antimicrobial peptides (AMPs) are known to be able to kill multidrug-resistant bacteria and, therefore, of interest to be developed into antimicrobial drugs. Proteolytic stability and toxicities of these peptides are challenges to overcome, and one strategy frequently used to address stability is cyclization. Here we introduced a disulfide-bond to cyclize a potent and nontoxic 9mer peptide and, in addition, as a proof-of-concept study, grafted this peptide into loop 6 of the cyclotide MCoTI-II. This is the first time an antimicrobial peptide has been successfully grafted onto the cyclotide scaffold. The disulfide-cyclized and grafted cyclotide showed moderate activity in broth and strong activity in 1/5 broth against clinically relevant resistant pathogens. The linear peptide showed superior activity in both conditions. The half-life time in 100% human serum was determined, for the linear peptide, to be 13 min, for the simple disulfide-cyclized peptide, 9 min, and, for the grafted cyclotide 7 h 15 min. The addition of 10% human serum led to a loss of antimicrobial activity for the different organisms, ranging from 1 to >8-fold for the cyclotide. For the disulfide-cyclized version and the linear version, activity also dropped to different degrees, 2 to 18-fold, and 1 to 30-fold respectively. Despite the massive difference in stability, the linear peptide still showed superior antimicrobial activity. The cyclotide and the disulfide-cyclized version demonstrated a slower bactericidal effect than the linear version. All three peptides were stable at high and low pH, and had very low hemolytic and cytotoxic activity.
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DOI：
10.3390/molecules22071217
发表时间：
2017-07-20
期刊：
Molecules (Basel, Switzerland)
影响因子：
--
作者：
Falanga A;Nigro E;De Biasi MG;Daniele A;Morelli G;Galdiero S;Scudiero O
通讯作者：
Scudiero O
影响因子：
4.6
作者：
Huang YH;Henriques ST;Wang CK;Thorstholm L;Daly NL;Kaas Q;Craik DJ
通讯作者：
Craik DJ
DOI：
10.1073/pnas.0504613102
发表时间：
2005-09-27
影响因子：
11.1
作者：
Clark, RJ;Fischer, H;Craik, DJ
通讯作者：
Craik, DJ
影响因子：
5.6
作者：
Craik, DJ;Daly, NL;Waine, C
通讯作者：
Waine, C
影响因子：
2.9
作者：
Heitz, A;Hernandez, JF;Chiche, L
通讯作者：
Chiche, L