Abstract:
:The rise of antibiotic resistance demands the acceleration of molecular diversification strategies to inspire new chemical entities for antibiotic medicines. We report here on the large-scale engineering of ribosomally synthesized and post-translationally modified antimicrobial peptides carrying the ring-forming amino acid lanthionine. New-to-nature variants featuring distinct properties were obtained by combinatorial shuffling of peptide modules derived from 12 natural antimicrobial lanthipeptides and processing by a promiscuous post-translational modification machinery. For experimental characterization, we developed the nanoFleming, a miniaturized and parallelized high-throughput inhibition assay. On the basis of a hit set of >100 molecules, we identified variants with improved activity against pathogenic bacteria and shifted activity profiles, and extrapolated design guidelines that will simplify the identification of peptide-based anti-infectives in the future.
journal_name
Nat Chem Bioljournal_title
Nature chemical biologyauthors
Schmitt S,Montalbán-López M,Peterhoff D,Deng J,Wagner R,Held M,Kuipers OP,Panke Sdoi
10.1038/s41589-019-0250-5subject
Has Abstractpub_date
2019-05-01 00:00:00pages
437-443issue
5eissn
1552-4450issn
1552-4469pii
10.1038/s41589-019-0250-5journal_volume
15pub_type
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