Molecular Basis of Selectivity and Activity for the Antimicrobial Peptide Lynronne-1 Informs Rational Design of Peptide with Improved Activity.
Molecular Basis of Selectivity and Activity for the Antimicrobial Peptide Lynronne-1 Informs Rational Design of Peptide with Improved Activity.
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DOI：
10.1002/cbic.202100151
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发表时间：
2021-07-15
期刊：
影响因子：
--
通讯作者：
Dixon AM
中科院分区：
文献类型：
--
作者：
Jayawant ES;Hutchinson J;Gašparíková D;Lockey C;Pruñonosa Lara L;Guy C;Brooks RL;Dixon AM
抗生素耐药性对人类健康构成重大威胁，天然产物仍然是新型抗菌化合物的最佳来源。抗菌肽（AMP）是具有巨大临床应用潜力的天然产物，因为它们体积小、易于定制且具有广谱活性。 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，我们使用溶液核磁共振波谱研究了 Lynronne-1 的结构，并鉴定了包含所有六个阳离子残基的 13 个残基两亲螺旋。我们使用生物物理方法来观察对阴离子脂质存在的选择性折叠、膜分配和膜裂解。我们将对 Lynronne-1 结构的理解转化为设计疏水螺旋面大小不同的肽。这些肽在体外和体内表现出预测的连续膜裂解活性，并产生了一种新的 AMP，其针对鲍曼不动杆菌的活性提高了 4 倍，针对金黄色葡萄球菌的活性提高了 32 倍。在这里，我们描述了 Lynronne-1 的生物物理特征，Lynronne-1 是牛瘤胃微生物组中发现的一种抗菌肽。我们揭示了包含所有六个阳离子残基的两亲性螺旋的位置，并观察了脂质选择性折叠、膜结合和裂解。我们的结构数据用于设计三种改变疏水螺旋面尺寸的变体，其中一种在体内的活性提高了 32 倍。
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. Here we describe the biophysical characterization of Lynronne‐1, an antimicrobial peptide found in the bovine rumen microbiome. We reveal the location of an amphipathic helix containing all six cationic residues, and observe lipid‐selective folding, membrane‐binding and lysis. Our structural data were used to design three variants with changes in the size of the hydrophobic helical face, one of which yielded 32‐fold improved activity in vivo.
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影响因子：
4.3
作者：
Li J;Koh JJ;Liu S;Lakshminarayanan R;Verma CS;Beuerman RW
通讯作者：
Beuerman RW
影响因子：
4.8
作者：
Kondejewski, LH;Jelokhani-Niaraki, M;Hodges, RS
通讯作者：
Hodges, RS
影响因子：
4
作者：
Marr, Alexandra K.;Gooderham, William J.;Hancock, Robert E. W.
通讯作者：
Hancock, Robert E. W.
影响因子：
4.9
作者：
Giacometti, A;Cirioni, O;Scalise, G
通讯作者：
Scalise, G
影响因子：
2.4
作者：
Kucerka, N;Tristram-Nagle, S;Nagle, JF
通讯作者：
Nagle, JF