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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.
Zarena, D; Mishra, Biswajit; Lushnikova, Tamara; Wang, Fangyu; Wang, Guangshun.
Afiliação
  • Zarena D; Department of Pathology and Microbiology, College of Medicine, University of Nebraska Medical Center , 986495 Nebraska Medical Center, Omaha, Nebraska 68198-6495, United States.
  • Mishra B; Department of Physics, JNTUA College of Engineering , Anantapur 515002, India.
  • Lushnikova T; Department of Pathology and Microbiology, College of Medicine, University of Nebraska Medical Center , 986495 Nebraska Medical Center, Omaha, Nebraska 68198-6495, United States.
  • Wang F; Department of Pathology and Microbiology, College of Medicine, University of Nebraska Medical Center , 986495 Nebraska Medical Center, Omaha, Nebraska 68198-6495, United States.
  • Wang G; Department of Pathology and Microbiology, College of Medicine, University of Nebraska Medical Center , 986495 Nebraska Medical Center, Omaha, Nebraska 68198-6495, United States.
Biochemistry ; 56(31): 4039-4043, 2017 08 08.
Article em En | MEDLINE | ID: mdl-28731688
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 communication presents the three-dimensional structure of an eight-residue Trp-rich peptide (WWWLRKIW-NH2 with 50% W) determined by the improved two-dimensional nuclear magnetic resonance method, which includes the measurements of 13C and 15N 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 π configuration with W2 as the horizontal bar and W1/W3 forming the two legs. An arginine scan reveals that the WWW motif is essential for killing methicillin-resistant Staphylococcus aureus USA300 and disrupting preformed bacterial biofilms. This unique π 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 I7 to R led to a potent antimicrobial and antibiofilm 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 via structure-activity relationship studies, and laid the foundation for engineering future antibiotics based on the WWW motif.
Assuntos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Oligopeptídeos / Desenho de Fármacos / Modelos Moleculares / Biofilmes / Peptídeos Catiônicos Antimicrobianos / Staphylococcus aureus Resistente à Meticilina / Antibacterianos Limite: Humans Idioma: En Ano de publicação: 2017 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Oligopeptídeos / Desenho de Fármacos / Modelos Moleculares / Biofilmes / Peptídeos Catiônicos Antimicrobianos / Staphylococcus aureus Resistente à Meticilina / Antibacterianos Limite: Humans Idioma: En Ano de publicação: 2017 Tipo de documento: Article