Escherichia coli Microcin B17 as a chassis for the development of novel antimicrobial peptides

Abstract

Abstract Antimicrobial resistance remains an urgent and growing global health problem. Peptides with antimicrobial activity are widespread in nature but are rarely harnessed for therapeutic applications, making them an underexplored and untapped resource. Many harbour post-translational modifications, which are essential for function and have evolved alongside specialized export and immunity machineries – leading to the current paradigm that natural sequences cannot be changed in vivo, and curtailing their development as antimicrobial agents. Nonetheless, we found sufficient ambiguity in literature to question if that remained true for E. coli microcin B17 (MccB17). We demonstrate that its natural machinery for synthesis, export, and immunity can be co-opted as a platform for novel azole-modified antimicrobial peptide discovery, exploring sequences unrelated to wild-type. We show a dense functional space, establishing the possibility that, through directed evolution, antimicrobial discovery could match the speed with which resistance emerges.