title: Mechanism of Four de Novo Designed Antimicrobial Peptides.
abstract: As pathogenic bacteria become resistant to traditional antibiotics, alternate approaches such as designing and testing new potent selective antimicrobial peptides (AMP) are increasingly attractive. However, whereas much is known regarding the relationship between the AMP sequence and potency, less research has focused on developing links between AMP properties, such as design and structure, with mechanisms. Here we use four natural AMPs of varying known secondary structures and mechanisms of lipid bilayer disruption as controls to determine the mechanisms of four rationally designed AMPs with similar secondary structures and rearranged amino acid sequences. Using a Quartz Crystal Microbalance with Dissipation, we were able to differentiate between molecular models of AMP actions such as barrel-stave pore formation, toroidal pore formation, and peptide insertion mechanisms by quantifying differential frequencies throughout an oscillating supported lipid bilayer. Barrel-stave pores were identified by uniform frequency modulation, whereas toroidal pores possessed characteristic changes in oscillation frequency throughout the bilayer. The resulting modes of action demonstrate that rearrangement of an amino acid sequence of the AMP resulted in identical overall mechanisms, and that a given secondary structure did not necessarily predict mechanism. Also, increased mass addition to Gram-positive mimetic membranes from AMP disruption corresponded with lower minimum inhibitory concentrations against the Gram-positive Staphylococcus aureus.
authors.affiliation: From the Department of Chemical and Biological Engineering, and Center for Biotechnology and Interdisciplinary Studies, Rensselaer Polytechnic Institute, Troy, New York 12180.
authors.forename: Brian
authors.initials: B
authors.lastname: Murray
authors.affiliation: From the Department of Chemical and Biological Engineering, and Center for Biotechnology and Interdisciplinary Studies, Rensselaer Polytechnic Institute, Troy, New York 12180.
authors.forename: C Seth
authors.initials: CS
authors.lastname: Pearson
authors.affiliation: From the Department of Chemical and Biological Engineering, and Center for Biotechnology and Interdisciplinary Studies, Rensselaer Polytechnic Institute, Troy, New York 12180.
authors.forename: Alexa
authors.initials: A
authors.lastname: Aranjo
authors.affiliation: From the Department of Chemical and Biological Engineering, and Center for Biotechnology and Interdisciplinary Studies, Rensselaer Polytechnic Institute, Troy, New York 12180.
authors.forename: Dinesh
authors.initials: D
authors.lastname: Cherupalla
authors.affiliation: From the Department of Chemical and Biological Engineering, and Center for Biotechnology and Interdisciplinary Studies, Rensselaer Polytechnic Institute, Troy, New York 12180 belfog@rpi.edu.
authors.forename: Georges
authors.initials: G
authors.lastname: Belfort
mesh_terms: D023181:Antimicrobial Cationic Peptides / Q000138:chemical synthesis / Q000737:chemistry*; D008051:Lipid Bilayers / Q000737:chemistry*; D008956:Models, Chemical; D058525:Quartz Crystal Microbalance Techniques
chemical_list: D023181:Antimicrobial Cationic Peptides; D008051:Lipid Bilayers
keywords: antimicrobial peptide (AMP); cell-penetrating peptide (CPP); lipid bilayer; peptide interaction; peptides