title: High-throughput discovery of broad-spectrum peptide antibiotics.
abstract: Membrane-permeabilizing peptide antibiotics are an underutilized weapon in the battle against drug-resistant microorganisms. This is true, in part, because of the bottleneck caused by the lack of explicit design principles and the paucity of simple high-throughput methods for selection. In this work, we characterize the requirements for broad-spectrum antimicrobial activity by membrane permeabilization and find that different microbial membranes have very different susceptibilities to permeabilization by individual antimicrobial peptides. Broad-spectrum activity requires only that an AMP have at least a small amount of membrane-permeabilizing activity against multiple classes of microbes, a feature that we show to be rare in a peptide library containing many members with species-specific activity. We compare biological and vesicle-based high-throughput strategies for selecting such broad-spectrum AMPs from combinatorial peptide libraries and demonstrate that a simple in vitro, lipid vesicle-based high-throughput screen is the most effective strategy for rapid discovery of novel, broad-spectrum antimicrobial peptides.
authors.affiliation: Department of Biochemistry, Tulane University Health Sciences Center, New Orleans, LA 70112, USA.
authors.forename: Ramesh
authors.initials: R
authors.lastname: Rathinakumar
authors.forename: William C
authors.initials: WC
authors.lastname: Wimley
mesh_terms: D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000494:pharmacology*; D003455:Cryptococcus neoformans / Q000187:drug effects; D004926:Escherichia coli / Q000187:drug effects; D008081:Liposomes / Q000737:chemistry; D019151:Peptide Library; D010455:Peptides / Q000737:chemistry / Q000494:pharmacology*; D010539:Permeability; D013211:Staphylococcus aureus / Q000187:drug effects
chemical_list: D000900:Anti-Bacterial Agents; D008081:Liposomes; D019151:Peptide Library; D010455:Peptides
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