Binary Encoding of Random Peptide Sequences for Selective and Differential Antimicrobial Mechanisms

Abstract Binary encoding of peptide sequences into differential antimicrobial mechanisms is reported. Such sequences are random in composition, but controllable in chain length, are assembled from the same two amino acids, but differ in the stereochemistry of one. Regardless of chirality, the sequences lyse bacteria including the “superbugs” methicillin‐resistant Staphylococcus aureus (MRSA) and vancomycin‐resistant Enterococci (VRE). Sequences with the same chirality, so‐called homochiral sequences, assemble into antimicrobial pores and form contiguous helices that are biologically promiscuous and hemolytic. By contrast, heterochiral sequences that lack such persistence selectively attack bacterial membranes without oligomerizing into visible pores. These results offer a mechanistic rationale for designing membrane‐selective and sequence‐independent antimicrobials.