Peptide Inhibitors of Bacterial Protein Synthesis with Broad Spectrum and SbmA-Independent Bactericidal Activity against Clinical Pathogens
Peptide Inhibitors of Bacterial Protein Synthesis with Broad Spectrum and SbmA-Independent Bactericidal Activity against Clinical Pathogens
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DOI：
10.1021/acs.jmedchem.0c00665
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发表时间：
2020-09-10
影响因子：
7.3
通讯作者：
Scocchi, Marco
中科院分区：
文献类型：
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作者：
Mardirossian, Mario;Sola, Riccardo;Scocchi, Marco
富含脯氨酸的抗菌肽（PrAMP）是开发新型抗菌药物的有前景的先导化合物；然而，它们的作用范围狭窄，因此受到限制。 PrAMP 可杀死与其核糖体结合并抑制蛋白质合成的细菌。在本研究中，合成了 PrAMP Bac7(1-16) 的 133 种衍生物，以鉴定核糖体失活和抗菌活性的关键残基。然后，构想出五种新的 Bac7(1-16) 衍生物，并通过抗菌和膜透化测定、X 射线晶体学和分子动力学模拟进行表征。一些衍生物表现出广谱活性，包括大肠杆菌、肺炎克雷伯菌、鲍曼不动杆菌、铜绿假单胞菌和金黄色葡萄球菌。五分之二的肽获得了微弱的膜扰动活性，同时保持了抑制蛋白质合成的能力。这些衍生物变得独立于天然 PrAMP 常用的 SbmA 转运蛋白，这表明它们获得了进入细菌细胞的新途径。 PrAMP 衍生化合物可能成为对抗抗生素耐药病原体的新一代抗菌剂。
Proline-rich antimicrobial peptides (PrAMPs) are promising lead compounds for developing new antimicrobials; however, their narrow spectrum of action is limiting. PrAMPs kill bacteria binding to their ribosomes and inhibiting protein synthesis. In this study, 133 derivatives of the PrAMP Bac7(1-16) were synthesized to identify the crucial residues for ribosome inactivation and antimicrobial activity. Then, five new Bac7(1-16) derivatives were conceived and characterized by antibacterial and membrane permeabilization assays, X-ray crystallography, and molecular dynamics simulations. Some derivatives displayed broad spectrum activity, encompassing Escherichia coli, Klebsiella pneumoniae, Acinetobacter baumanii, Pseudomonas aeruginosa, and Staphylococcus aureus. Two peptides out of five acquired a weak membrane-perturbing activity while maintaining the ability to inhibit protein synthesis. These derivatives became independent of the SbmA transporter, commonly used by native PrAMPs, suggesting that they obtained a novel route to enter bacterial cells. PrAMPderived compounds could become new-generation antimicrobials to combat antibiotic-resistant pathogens.