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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 and 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. [ABSTRACT FROM AUTHOR]