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Mimicry of Non-Ribosomally Produced Antimicrobials by Ribosomal Synthesis and Posttranslational Modification

30 Pages Posted: 7 May 2020 Sneak Peek Status: Under Review

See all articles by Xinghong Zhao

Xinghong Zhao

University of Groningen - Department of Molecular Genetics

Zhibo Li

University of Groningen - Department of Molecular Genetics

Oscar P. Kuipers

University of Groningen - Department of Molecular Genetics

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Abstract

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

Suggested Citation

Zhao, Xinghong and Li, Zhibo and Kuipers, Oscar P., Mimicry of Non-Ribosomally Produced Antimicrobials by Ribosomal Synthesis and Posttranslational Modification. Available at SSRN: https://ssrn.com/abstract=3581361 or http://dx.doi.org/10.2139/ssrn.3581361
This is a paper under consideration at Cell Press and has not been peer-reviewed.

Xinghong Zhao

University of Groningen - Department of Molecular Genetics ( email )

Netherlands

Zhibo Li

University of Groningen - Department of Molecular Genetics

Netherlands

Oscar P. Kuipers (Contact Author)

University of Groningen - Department of Molecular Genetics

Netherlands

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