The pi Configuration of the WWW Motif of a Short Trp-Rich Peptide Is Critical for Targeting Bacterial Membranes, Disrupting Preformed Biofilms, and Killing Methicillin-Resistant Staphylococcus aureus

文献类型： 外文期刊

第一作者： Zarena, D.

作者： Zarena, D.;Mishra, Biswajit;Lushnikoya, Tamara;Wang, Fangyu;Wang, Guangshun;Zarena, D.;Wang, Fangyu

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期刊名称：BIOCHEMISTRY （ 影响因子：3.162； 五年影响因子：3.045 ）

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收录情况： SCI

摘要： Tryptophan-rich peptides, being short and suitable for large-scale chemical synthesis, are attractive candidates for developing a new generation of antimicrobials to, combat antibiotic-resistant bacteria (superbugs). Although there are numerous pictures of the membrane bound structure of a single tryptophan (W), how multiple Trp amino acids assemble themselves and interact with bacterial membranes is poorly understood. This commuiiication presents the three-dimensional, structure of an eight-residue Tip-rich peptide (WWWLRKIW-NH2 with 50% deterthined by the improved two-dimensional nuclear magnetic resonance method, which includes the measurements of C-13 and N-15 chemical shifts at natural abundance. This peptide forms the shortest two-turn helix with a distinct amphipathic feature. A unique structural arrangement is identified for the Trp triplet, WWW, that forms a pi configuration with W2 as the horizontal bar and W-1/W-3 forming the two legs. An arginine scan reveals that the WWW motif is essential for killing methiciBin= resistant Staphylococcus,aureus USA300 and disrupting preformed bacterial hiofilms. This unique x configuration for the WWW motif is stabilized by aromatic aromatic, interactions as evidenced by ring current shifts as well as nuclear Overhauser effects. Because the WWW motif is maintained, a change of 17 to R led to a potent antimicrobial and antibiofilin peptide with 4-fold improvement in cell' selectivity. Collectively, this study elucidated' the structural basis of antibiofilm activity of the peptide, identified a better peptide candidate structure activity relationship studies, and laid the foundation for engineering future antibiotics based on the WWW motif.

分类号： Q5

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