Mimicry of Non-Ribosomally Produced Antimicrobials by Ribosomal Synthesis and Posttranslational Modification
30 Pages Posted: 7 May 2020 Sneak Peek Status: Under ReviewMore...
The group of non-ribosomally produced peptides (NRPs) forms a rich source of antibiotics, like daptomycin, vancomycin, teixobactin and many others. The difficulty to functionally express and engineer the corresponding large biosynthetic complexes is a bottleneck to develop novel variants of such peptides. Here, we apply a completely novel 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 synthesis (RiPPs), introducing several relevant modifications, such as dehydration and thioether-ring formation. Following this strategy, in two rounds peptides were engineered, with potent 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 posttranslational 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.
Keywords: Mimicry, NRPs, RiPPs, Antimicrobials, Biosynthetic
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