Mimicry of a Non-ribosomally Produced Antimicrobial, Brevicidine, by Ribosomal Synthesis and Post-translational Modification.

The group of bacterial non-ribosomally produced peptides (NRPs) forms a rich source of antibiotics, such as daptomycin, vancomycin, and teixobactin. The difficulty of functionally expressing and engineering the corresponding large biosynthetic complexes is a bottleneck in developing variants of such peptides. Here, we apply a strategy to synthesize mimics of the recently discovered antimicrobial NRP brevicidine. We mimicked the molecular structure of brevicidine by ribosomally synthesized, post-translationally modified peptide (RiPP) synthesis, introducing several relevant modifications, such as dehydration and thioether ring formation. Following this strategy, in two rounds peptides were engineered in vivo , which showed antibacterial activity against Gram-negative pathogenic bacteria susceptible to wild-type brevicidine. This study demonstrates the feasibility of a strategy to structurally and functionally mimic NRPs by employing the synthesis and post-translational modifications typical for RiPPs. This enables the future generation of large genetically encoded peptide libraries of NRP-mimicking structures to screen for antimicrobial activity against relevant pathogens. • Mimicry of NRPs by RiPP biosynthesis is a feasible strategy for drug discovery • The acyl chain of brevicidine can be mimicked by hydrophobic amino acid residues • The lactone ring of brevicidine can be functionally mimicked by a thioether ring • Engineered RiPPs display a similar antimicrobial mode of action as brevicidine Zhao et al. describe a strategy to synthesize mimics of the recently discovered antimicrobial non-ribosomal peptide, brevicidine. The engineered mimics show antimicrobial activities against pathogens susceptible to brevicidine, which demonstrate that conversion of NRPs to RiPPs is feasible and offer great opportunities for engineering a wide range of effective antibiotics. [ABSTRACT FROM AUTHOR]