Discovery of Next-Generation Antimicrobials through Bacterial Self-Screening of Surface-Displayed Peptide Libraries

Ashley T. Tucker, Sean P. Leonard, Cory D. DuBois, Gregory A. Knauf, Ashley L. Cunningham, Claus O. Wilke, M. Stephen Trent, Bryan W. Davies8,'Correspondence information about the author Bryan W. DaviesEmail the author Bryan W. Davies 8Lead Contact Publication stage: In Press Corrected Proof Discovery of Next-Generation Antimicrobials through Bacterial Self-Screening of Surface-Displayed Peptide Libraries DOI: http://dx.doi.org/10.1016/j.cell.2017.12.009 Highlights •Development of a high-throughput platform for discovery of antimicrobial peptides •Screening 800,000 peptides uncovered thousands of synthetic antimicrobial sequences •Lead peptides exhibit potent antimicrobial activity and distinctive mechanisms •Lead hit antimicrobial physicochemistry extends far beyond what nature has evolved Summary Peptides have great potential to combat antibiotic resistance. While many platforms can screen peptides for their ability to bind to target cells, there are virtually no platforms that directly assess the functionality of peptides. This limitation is exacerbated when identifying antimicrobial peptides because the phenotype, death, selects against itself and has caused a scientific bottleneck that confines research to a few naturally occurring classes of antimicrobial peptides. We have used this seeming dissonance to develop Surface Localized Antimicrobial Display (SLAY), a platform that allows screening of unlimited numbers of peptides of any length, composition, and structure in a single tube for antimicrobial activity. Using SLAY, we screened ∼800,000 random peptide sequences for antimicrobial function and identified thousands of active sequences, dramatically increasing the number of known antimicrobial sequences. SLAY hits present with different potential mechanisms of peptide action and access to areas of antimicrobial physicochemical space beyond what nature has evolved. Keywords: antibiotic resistance, bacteria, high-throughput screening, drug discovery, infectious diseases