Institute of Biochemistry, Christian-Albrechts-University, Olshausenstr. 40, 24098 Kiel, Germany.
Biochem Biophys Res Commun. 2012 Oct 12;427(1):207-11. doi: 10.1016/j.bbrc.2012.09.052. Epub 2012 Sep 18.
Antimicrobial peptides participate in the first line of defence of many organisms against pathogens. In humans, the family of β-defensins plays a pivotal role in innate immunity. Two human β-defensins, β-defensin-2 and -3 (HBD2 and HBD3), show substantial sequence identity and structural similarity. However, HBD3 kills Staphylococcus (S.) aureus with a 4- to 8-fold higher efficiency compared to HBD2, whereas their activities against Escherichia (E.) coli are very similar. The generation of six HBD2/HBD3-chimeric molecules led to the identification of distinct molecular regions which mediate their divergent killing properties. One of the chimeras (chimera C3) killed both E. coli and S. aureus with an even higher efficacy compared to the wild-type molecules. Due to the broad spectrum of its antimicrobial activity against many human multidrug-resistant pathogens, this HBD2/HBD3-chimeric peptide represents a promising candidate for a new class of antibiotics. In order to investigate the structural basis of its exceptional antimicrobial activity, the peptide's tertiary structure was determined by NMR spectroscopy, which allowed its direct comparison to the published structures of HBD2 and HBD3 and the identification of the activity-increasing molecular features.
抗菌肽参与许多生物体对抗病原体的第一道防线。在人类中，β-防御素家族在先天免疫中起着关键作用。两种人类β-防御素，β-防御素-2 和 -3（HBD2 和 HBD3），具有显著的序列同一性和结构相似性。然而，与 HBD2 相比，HBD3 对金黄色葡萄球菌（S. aureus）的杀伤效率高 4-8 倍，而它们对大肠杆菌（E. coli）的活性非常相似。生成的六种 HBD2/HBD3 嵌合分子鉴定出介导其不同杀伤特性的独特分子区域。其中一种嵌合体（嵌合体 C3）对大肠杆菌和金黄色葡萄球菌的杀伤效率比野生型分子更高。由于其对许多人类多药耐药病原体具有广谱的抗菌活性，这种 HBD2/HBD3 嵌合肽代表了一类新抗生素的有前途的候选物。为了研究其非凡的抗菌活性的结构基础，通过 NMR 光谱学确定了该肽的三级结构，这使其能够与已发表的 HBD2 和 HBD3 结构直接比较，并确定了增加活性的分子特征。
