The π 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

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

来源：Biochemistry, 2017, 56(31): 4039-4043.

DOI：10.1021/acs.biochem.7b00456

• ANTIMICROBIAL PEPTIDES
• DATABASE
• MECHANISMS
• LL-37

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.

• 出版日期2017-8-8
• 单位河南省农业科学院