Proline-Rich Peptides with Improved Antimicrobial Activity against E. coli, K. pneumoniae, and A. baumannii.,ChemMedChem

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Proline-Rich Peptides with Improved Antimicrobial Activity against E. coli, K. pneumoniae, and A. baumannii.
ChemMedChem ( IF 3.6 ) Pub Date : 2019-11-14 , DOI: 10.1002/cmdc.201900465
Mario Mardirossian ₁ , Riccardo Sola ₁ , Bertrand Beckert ₂ , Dominic W P Collis ₃ , Adriana Di Stasi ₁ , Federica Armas ₁ , Kai Hilpert ₄ , Daniel N Wilson ₂ , Marco Scocchi ₁

Affiliation

Proline-rich antimicrobial peptides (PrAMPs) are promising agents to combat multi-drug resistant pathogens due to a high antimicrobial activity, yet low cytotoxicity. A library of derivatives of the PrAMP Bac5(1-17) was synthesized and screened to identify which residues are relevant for its activity. In this way, we discovered that two central motifs -PIRXP- cannot be modified, while residues at N- and C- termini tolerated some variations. We found five Bac5(1-17) derivatives bearing 1-5 substitutions, with an increased number of arginine and/or tryptophan residues, exhibiting improved antimicrobial activity and broader spectrum of activity while retaining low cytotoxicity toward eukaryotic cells. Transcription/translation and bacterial membrane permeabilization assays showed that these new derivatives still retained the ability to strongly inhibit bacterial protein synthesis, but also acquired permeabilizing activity to different degrees. These new Bac5(1-17) derivatives therefore show a dual mode of action which could hinder the selection of bacterial resistance against these molecules.

中文翻译：

富含脯氨酸的肽，对大肠杆菌、肺炎克雷伯菌和鲍曼不动杆菌具有改进的抗菌活性。

富含脯氨酸的抗菌肽 (PrAMP) 具有高抗菌活性和低细胞毒性，是对抗多重耐药病原体的有前途的药物。合成并筛选了 PrAMP Bac5(1-17) 衍生物文库，以确定哪些残基与其活性相关。通过这种方式，我们发现两个中心基序-PIRXP-不能被修饰，而N-和C-末端的残基可以容忍一些变化。我们发现五种 Bac5(1-17) 衍生物具有 1-5 个取代，精氨酸和/或色氨酸残基数量增加，表现出改善的抗菌活性和更广的活性谱，同时保留对真核细胞的低细胞毒性。转录/翻译和细菌膜透化实验表明，这些新衍生物仍然保留了强烈抑制细菌蛋白质合成的能力，但也获得了不同程度的透化活性。因此，这些新的 Bac5(1-17) 衍生物表现出双重作用模式，可能阻碍细菌对这些分子的耐药性的选择。

更新日期：2019-11-14

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