Department of Chemistry, University of Warwick, Gibbett Hill Road, Coventry, CV4 7AL, UK.
SynBio Doctoral Training Centre, University of Warwick, Gibbet Hill Road, Coventry, CV4 7AL, UK.
Chembiochem. 2021 Jul 15;22(14):2430-2439. doi: 10.1002/cbic.202100151. Epub 2021 Jun 8.
Antibiotic resistance is a significant threat to human health, with natural products remaining the best source for new antimicrobial compounds. Antimicrobial peptides (AMPs) are natural products with great potential for clinical use as they are small, amenable to customization, and show broad-spectrum activities. Lynronne-1 is a promising AMP identified in the rumen microbiome that shows broad-spectrum activity against pathogens such as methicillin-resistant Staphylococcus aureus and Acinetobacter baumannii. Here we investigated the structure of Lynronne-1 using solution NMR spectroscopy and identified a 13-residue amphipathic helix containing all six cationic residues. We used biophysical approaches to observe folding, membrane partitioning and membrane lysis selective to the presence of anionic lipids. We translated our understanding of Lynronne-1 structure to design peptides which varied in the size of their hydrophobic helical face. These peptides displayed the predicted continuum of membrane-lysis activities in vitro and in vivo, and yielded a new AMP with 4-fold improved activity against A. baumannii and 32-fold improved activity against S. aureus.
抗生素耐药性是对人类健康的重大威胁，天然产物仍然是新的抗菌化合物的最佳来源。抗菌肽 (AMPs) 是具有巨大临床应用潜力的天然产物，因为它们体积小、易于定制，并具有广谱活性。Lynronne-1 是在瘤胃微生物组中发现的一种很有前途的 AMP，它对耐甲氧西林金黄色葡萄球菌和鲍曼不动杆菌等病原体具有广谱活性。在这里，我们使用溶液 NMR 光谱研究了 Lynronne-1 的结构，并确定了一个包含所有六个阳离子残基的 13 残基两亲性螺旋。我们使用生物物理方法观察到折叠、膜分配和膜裂解选择性地存在阴离子脂质。我们将我们对 Lynronne-1 结构的理解转化为设计肽，这些肽在疏水性螺旋面的大小上有所不同。这些肽在体外和体内均表现出预测的膜裂解活性连续体，并产生了一种新的 AMP，对鲍曼不动杆菌的活性提高了 4 倍，对金黄色葡萄球菌的活性提高了 32 倍。
